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Posted 09 September 2014 - 07:10 PM

Quote Moderation  - I've moved some posts from a similar discussion  here. The title has also been modified to reflect the additions.

Preliminary indications that 3-Bromopyruvate might be a broadly effective cancer treatment has been building over the last

15 years. It is time that a topic on this forum considered the potential benefits and risks of this molecule.

3-Bromopyruvate appears to interfere with cancer cells energy supply through blocking glycolysis.

Some topics of interest concerning 3-Bromopyruvate that might be discussed here include:

- The FDA's granting of orphan drug status for 3-Bromopyruvate in pancreatic cancer (04/2014) and liver cancer (03/2013).

- The phase 1 trial that was authorized by the FDA over a year ago.

- The recently published human case study of a metastatic melanoma patient who after treatment with 3-Bromopyruvate and paracetamol (which depletes tumor glutathione)

experienced a decline in serum lactate dehydrogenase (LDH) from over 4200 U/L to 12 U/L.

- A published human case study of 3-Bromopyruvate in liver cancer that also showed remarkable anti-cancer results.

- The possible risks that 3-Bromopyruvate poses for cognitive impairment. Mouse models have found that injection of 3-Bromopyruvate

into the brain causes an Alzheimer-like phenotype.

Edited by niner, 06 February 2015 - 05:04 PM.


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#2 joelcairo
Posted 18 September 2014 - 03:15 PM I'd be surprised if there was any Alzheimer's risk. A cancer patient would only take 3-BP for a short period of time.
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#3 mag1
Posted 18 September 2014 - 04:49 PM Agreed. It would be an easy decision to choose 3-Bromopyruvate treatment against a theoretical risk of Alzheimer's disease.
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Pharmacol Biochem Behav. 1995 Aug;51(4):917-22. Holeboard maze-learning deficits and brain monoaminergic neurotransmitter concentrations in rats after intracerebroventricular injection of 3-bromopyruvate.

The mice received 2 injections of 0.2 mumol  3-Bromopyruvate directly into their cerebral ventricles. 10 weeks later they displayed cognitive

impairment related to a cholinergic deficit connected to glucose metabolism. The article suggests that 3-Bromopyruvate could be used as an animal for Alzheimer's disease. Such a problem would be avoided if 3-Bromopyruvate were loaded into minicells.A 250 microgram cancer treatment with 3-Bromopyruvate in minicells would not likely cause any side-effects. Edited by mag1, 18 September 2014 - 04:51 PM.


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#4 mag1
Posted 04 October 2014 - 02:10 PM The patent for 3-Bromopyruvate as a cancer therapy described how intra-arterial injections to the liver caused the regression
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of large tumours and long term survival of animals. However, when 3-Bromopyruvate was injected systemically there was

no regression of liver tumours, though it did appear to suppress the development of lung metastases.

The first published human case study of 3-Bromopyruvate also used an intra-arterial injection method to treat liver cancer.

Yet, the recently published human case study in metastatic melanoma combined a GSH depletor and intravenous 3-Bromopyruvate

administration. This resulted in a very large anti-cancer effect.

A published study found that 3-Bromopyruvate when used as an inhalation therapy could effectively suppress lung tumour

growth in mice.

Could someone give an opinion as whether 3-Bromopyruvate could be a universal cancer cure given as a systematic therapy (as it is promoted on some websites) or whether it could have a more limited use as a site specific anti-cancer therapy ( for example, only injected into a liver artery etc.)?
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#5 mag1
Posted 18 January 2015 - 02:37 PM I would be interested in the use of transplanted mitochondria for cancer treatment.
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If mitochondria could be engineered that would self-destruct when given some signal (for example,

in the presence of mutated p53), then cancer cells could be deprived of their energy source.

Current cancer treatments (e.g. 3-Bromopyruvate) have shown impressive clinical results when shutting

down cellular respiration.

{It is also of note that a clinical trial with donated blood from younger people is in the works for Alzheimer's disease.}
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#6 pone11
Posted 18 January 2015 - 03:59 PM mag1, on 18 Jan 2015 - 3:37 PM, said: I would be interested in the use of transplanted mitochondria for cancer treatment.
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If mitochondria could be engineered that would self-destruct when given some signal (for example,

in the presence of mutated p53), then cancer cells could be deprived of their energy source.

Current cancer treatments (e.g. 3-Bromopyruvate) have shown impressive clinical results when shutting

down cellular respiration.

{It is also of note that a clinical trial with donated blood from younger people is in the works for Alzheimer's disease.} Can someone clarify this, because I thought the entire mode of operation of cancer was to shut down mitochondria and to use glycolysis OUTSIDE of the mitochondrial environment.

A drug that shuts down mitochondria would on face value simply enhance the glycolysis that feeds the cancer. It would be a catastrophic mistake.

If you believe Warburg's theories about cancer as a metabolic disease, the therapy that has merit would in fact be the opposite. You would want to upregulate aerobic metabolism and use of oxygen. There is some support for that in the literature by inserting healthy mitochondria into cancer cells:

http://www.ncbi.nlm....pubmed/23080556

Since cancer involves potential DNA modifications, it's not clear to me that simply replacing the mitochondria with new ones accomplishes this. You need to force the entire cancerous cell to upregulate its use of oxygen and downregulate glycolysis.

3-Bromopyruvate is a wonderful agent, but it does not act by denying cancer mitochondrial energy. It is an alkylating agent and may act by inhibiting the HK2 enzyme that cancer cells use to immortalize themselves and block apoptosis:

http://link.springer...0863-012-9425-4

Note the work of people like Dominic D'Agostino in Florida, who are now extending on Warburg's work and testing metabolic therapies. Dominic's lab has been using ketogenic diets, hyperbaric oxygen, and ketone supplements that boost ketones without dietary inputs. Here is a good overview of his work and early results, which are extremely impressive:

Dominic is very promotional for his lab, and you will find dozens of podcasts and Youtube videos with him advocating his work. Honestly if I was a billionaire I would fund him.

Edited by pone11, 18 January 2015 - 04:10 PM.


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#7 mag1
Posted 18 January 2015 - 04:27 PM Cancer cells use a 50 50 energy mix from OXPHOS and glycolysis. (Normal cells use a 95 5 energy mix)
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Selectively, removing the OXPHOS energy input from cancer cells would likely result in an overwhelming stress to

cancer cells. This energy crisis would result in the immediate destruction of the cancer cells.

The engineered mitochondria could be delivered to a patient as a "pro-drug". A signal molecule could then shut off the

mitochondria in cancer cells (e.g. cells with mutated p53 etc.).

The cancer therapy 3-Bromopyruvate which interferes with cellular respiration (specifically through the mitochondria) has shown dramatic results.

Consider:

Chin J Cancer. 2014 Jul;33(7):356-64. doi: 10.5732/cjc.013.10111. Epub 2014 Mar 14.

Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study

There are other 3-Bromopyruvate combinations including salinomycin, ketone therapy etc..


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#8 pone11
Posted 18 January 2015 - 04:55 PM mag1, on 18 Jan 2015 - 5:27 PM, said: Cancer cells use a 50 50 energy mix from OXPHOS and glycolysis. (Normal cells use a 95 5 energy mix)
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Selectively, removing the OXPHOS energy input from cancer cells would likely result in an overwhelming stress to

cancer cells. This energy crisis would result in the immediate destruction of the cancer cells.

The engineered mitochondria could be delivered to a patient as a "pro-drug". A signal molecule could then shut off the

mitochondria in cancer cells (e.g. cells with mutated p53 etc.).

The cancer therapy 3-Bromopyruvate which interferes with cellular respiration (specifically through the mitochondria) has shown dramatic results.

Consider:

Chin J Cancer. 2014 Jul;33(7):356-64. doi: 10.5732/cjc.013.10111. Epub 2014 Mar 14.

Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study

There are other 3-Bromopyruvate combinations including salinomycin, ketone therapy etc.. Think about what you just said. Cancer cells upregulate glycolysis from 5% of energy used in the cell to 50%. So your solution to cancer is to destroy the remaining 50% attributable to aerobic metabolism by downregulation of oxidative phosphorylation ("OXPHOS") and making glycolysis closer to 100% of the cells energy needs? That's 100% the opposite approach of what the literature suggests works.

You are not summarizing the metastatic melanoma study correctly. It's true that 3HP downregulated OXPHOS, but this was "In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH)...." So 3BP attacks the cancer by denying it glycolysis, and naturally since the cancer uses the HK2 enzyme to control activity of the mitochondria, a drug like 3BP that downregulates HK2 is going to selectively deny the cancer access to all energy sources, including OXPHOS. That's a side-effect, NOT the primary mechanism.

I have a metabolic disorder - now partly under control - that shifted my body into glycolysis. I can tell you that getting even 25% of your energy from glycolysis is like setting your body on fire. It's like someone has taken a needle and injected acid right into your brain and systemic circulation. You can't move; you can't think. It's overwhelming. The effects of high glycolysis levels on cancer patients is devastating. A therapy that downregulated OXPHOS without also targeting glycolysis would be a quick death sentence, and at minimum the patient would be in agony. I say that from personal experience, but the literature is quite clear that cancer is about the upregulation of glycolysis, and the therapy you are suggesting is about selectively denying the cancer cells energy from all sources.

Your choice of studies here is unfortunate since it is a report about how 3BP largely failed to impact the human patient's cancer, which was unfortunately quite advanced at the time they began therapy. The study I quoted from Peter Pedersen is a better overview of all of the 3BP modalities.

Edited by pone11, 18 January 2015 - 04:57 PM.


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#9 mag1
Posted 18 January 2015 - 05:14 PM I am very unsure about these comments concerning OXPHOS. I had thought that if one were to remove the mitochondrial
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energy input from the cancer cell, then this would be sufficient to destroy the cancer cell. It is notable that the suggestion is to selectively

remove half the energy supply from the cancer cell and not from the other cells of the body.

Cancer metabolism, stemness and tumor recurrence

Cell Cycle. May 1, 2013; 12(9): 1371–1384.

..."Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.”

The article with the cancer patient which used 3-Bromopyruvate resulted in an overwhelmingly massive cancer response. Figure 3 from the article shows that the patient's cancer was essentially metabolically cured after 3 combination treatments with 3BP. The patient's LDH level went from 1800 to 12 after those three doses. The article noted that the patient did not actually die from cancer, as no metabolically cancer was present at death. In fact, the patient died from hypoxia.
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#10 pone11
Posted 18 January 2015 - 05:43 PM mag1, on 18 Jan 2015 - 6:14 PM, said: I am very unsure about these comments concerning OXPHOS. I had thought that if one were to remove the mitochondrial
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energy input from the cancer cell, then this would be sufficient to destroy the cancer cell. It is notable that the suggestion is to selectively

remove half the energy supply from the cancer cell and not from the other cells of the body.

Cancer metabolism, stemness and tumor recurrence

Cell Cycle. May 1, 2013; 12(9): 1371–1384.

..."Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.”

The article with the cancer patient which used 3-Bromopyruvate resulted in an overwhelmingly massive cancer response. Figure 3 from the article shows that the patient's cancer was essentially metabolically cured after 3 combination treatments with 3BP. The patient's LDH level went from 1800 to 12 after those three doses. The article noted that the patient did not actually die from cancer, as no metabolically cancer was present at death. In fact, the patient died from hypoxia. The "Cancer metabolism, stemness and tumor recurrence" study is really interesting:

http://www.ncbi.nlm....les/PMC3674065/

From that study:

"Cancer cells have high bioenergetic requirements needed to maintain cell growth. Glycolysis with generation of lactate and reduced mitochondrial oxidative phosphorylation metabolism (OXPHOS) is commonly found in carcinoma cells in culture.  OXPHOS generates more ATP per molecule of glucose than glycolysis with lactate generation and hence it is unclear why some cells would use a metabolically inefficient pathway. It has been hypothesized that glycolysis may confer a growth and survival advantage, although the mechanism is unknown."

This study is VERY interesting, and it paints a very complex picture of what cancer does. It suggests that the most lethal cancers have a core set of cells that emphasize OXPHOS, but that a key critical component of the complex is a set of surrounding cells that are glycolytic and feed lactate and ketones to the OXPHOS cells. From your study:

"A significant subset of HNSCC tumors have a large glycolytic carcinoma cell compartment as measured by MCT4 expression and are associated with a statistically significantly decrease in DFS (Disease Free Survival). It may be that these tumors are more aggressive, because they generate oxidative stress, lactate and ketone bodies to fuel mitochondrial metabolism (OXPHOS) in adjacent proliferating epithelial cancer cells with high MCT1 expression."

So far, all of your studies confirm that cancer is about glycolysis, and that it is the glycolytic effect that causes the upregulation of cancer-controlled mitochondria.

What I take away from your studies is that cancer uses HK2 enzymes to control the mitochondria. Drugs like 3BP that downregulate HK2 interfere with glycolysis in the cancer cell and downregulate mitochondria at the same time.

Your studies are important, because they suggest that cancer is very good at both upregulation of glycolysis, but it then uses that energy to produce additional energy in mitochondria. I wasn't aware of that before, so thank you.

I would beg you to please listen to Dominic's presentation that I linked. The clinical outcomes they achieved by starving glycolysis are extremely impressive.

Edited by pone11, 18 January 2015 - 05:48 PM.


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#11 mag1
Posted 18 January 2015 - 06:08 PM The below 2 citations are reports of patients with severe cancer who received 3-Bromopyruvate and had very large cancer responses. Could someone confirm that the second article (July 2014) treated metastatic cancer using 3-BrP delivered only IV?
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The Johns Hopkins reports did not report such an outcome. In their reported research, the tumors were not treated via systemic therapy. Instead, in one instance they stopped circulation to the liver of experimental animals and then applied a treatment of 3BrP. Comments in their research raised doubts as to whether 3BrP would be successful if given systemically.

The anti-cancer effect achieved in the July 2014 article seems to be truly remarkable. Severe metastatic illness appears to have been cured using only IV BrP and paracetamol. The 3 combination doses of 3BrP and paracetamol appear to have had an overwhelming anti-tumor effect.

A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr. 2012 Feb;44(1):163-70. doi: 10.1007/s10863-012-9417-4. Epub 2012 Feb 11.

Chin J Cancer. 2014 Jul;33(7):356-64. doi: 10.5732/cjc.013.10111. Epub 2014 Mar 14. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study
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#12 resveratrol_guy
Posted 19 January 2015 - 06:44 PM I agree: the Dominic D'Agostino video is revolutionary, even for those of us already familiar with the ketogenic or paleo diets. This is an outstanding contribution, so thanks for posting.
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One thing that he said really blew me away (paraphrasing): transplanting cancer mitochondria into good cells resulted in cancer, even though transplanting cancer nuclear DNA into good cells did not. This begs the question: is there a more direct kinetic kill option here?

In particular: Can we use selective thermolysis to obliviate glycolytic (Warburg glycopathcological) mitochrondria? In other words, can we use a strategy similar to what the SENS team investigated for lipofuscin destruction using specific wavelengths of light, or what Yoav Medan used for ultrasonic tumor ablation -- but in this case, to selectively destroy mitochondria? One can imagine a whole body "scanner" which would bathe the patient in some specific wavelength of energy (photons, ultrasound, or something else). The viability of this strategy depends upon glycopathcological mitochrondria having distinct physical characteristics. This is more plausible than it sounds, on account of the deterioration of the cristae (interior mitochondrial membranes) @ 34:30 in the video, which might change the resonant frequencies of the encapsulating membrane as a whole. For example, if a normal mitochondrion explodes due to membrane resonance at 80 +/- 5 KHz, then maybe a bad one explodes at 93 +/- 5 KHz, in which case, we bathe the patient in the latter for some particular amount of time. Collateral damage might occur if the frequency domains overlap, but that might be desirable to the extent that it would destroy precancerous mitochondria as well. This ought to be relatively cheap to investigate.

Conversely, by analyzing the absorption spectrum, we might be able to use the ablation machine as a cancer detector.

All in all, kinda like this one currently in use on Elysium.

Edited by resveratrol_guy, 19 January 2015 - 07:07 PM.


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#13 pone11
Posted 19 January 2015 - 10:33 PM mag1, on 18 Jan 2015 - 7:08 PM, said: The below 2 citations are reports of patients with severe cancer who received 3-Bromopyruvate and had very large cancer responses. Could someone confirm that the second article (July 2014) treated metastatic cancer using 3-BrP delivered only IV? Based on the interesting 3BP research you posted, I contacted Dominic D'Agostino to see if his group is researching 3BP. He indicated that they are starting to look at lonidamine, which is a similar drug that selectively targets the hexokinase 2 enzyme in cancer. He does not have published studies yet, just abstracts. He only has in vivo data and they need funding to do animal studies. He indicated the data they have is very compelling.
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I would say you have a winner there with 3BP and just passing the pointer to lonidamine for your further research as well. Really any hexokinase 2 inhibitor is worth your time to research.

And if we have any billionaires here who want to fund Dominic's work, contact me by private messaging and I'll make an introduction. I can say that Dominic strikes me as the kind of young researcher who has a shot at curing cancer. He is super smart and very wise about how he funds research (e.g., getting the Navy to fund hyperbaric oxygen studies, which he then leveraged into oxygen therapy research for cancer). But - most importantly - he has the right idea. After 20 years of wasting billions of dollars on genetic cures to cancer, we finally have researchers coming back to Warburg's original idea that cancer is a metabolic disorder. Some combination of oxygen therapies, selective downregulation of energy production inside the cancer cell, dietary control to reduce glucose available to the cancer, etc, has a real shot at tripling lifespan expectancy for many cancers, just by starving their growth. Looking at the dietary issue alone, I cannot help but be amazed that Dominic figured out a way to produce a ketone ester that - taken orally - will raise ketone levels for hours, thereby allowing the person to live on ketone energy and sending their glucose levels very low without any metabolic discomfort to the brain or normal cellular metabolism. That ester by itself would be a huge accomplishment if commercialized, and he did that just to help prove a point in a larger study about cancer. Dominic gets stuff done.

Edited by pone11, 19 January 2015 - 10:36 PM.


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#14 mag1
Posted 19 January 2015 - 11:00 PM http://www.dayspring...-cancer-clinic/
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http://www.digitaljo....com/pr/2220319*Informative x 1
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#15 seivtcho
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 01:59 AM By the way, aren't this thing about the mitochondria and the cancer off-topic for mitochondria transplants? Why not you make another topic for that?
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#16 resveratrol_guy
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 01:55 PM mag1, on 20 Jan 2015 - 12:00 AM, said: http://www.dayspring...-cancer-clinic/
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http://www.digitaljo....com/pr/2220319 Good find, if these are to be believed.

"Founded in the U.S. 12 years ago, Cancer Treatment Institute of Colombia in Bogota treats cancer using novel cancer drugs and image-guided ablation with tumor vaccine." Yeah, I think these guys get it: the worst thing you can do with a "miracle" cancer drug is to use it as monotherapy. (Has the history of antibiotics taught us nothing?) Leave it to one of the most unstable countries in Latin America to light the way to serious gains against cancer, while we sit here in the US shuffling papers around antiquated tumor-specific approaches, throwing patients from one silo to another while the left hand doesn't know what the right hand is doing.

As they apparently realized long ago, we need to use 3BP (if it works as advertised) pursuant to physical tumor destruction via surgical excision with positive margins, irreversible electroporesis, ultrasound thermolysis, or whatever. This is basic math: exponentially fewer surviving cancer cells means that the remission threshold for 3BP to overcome is just that much lower. We could finish the job with a vaccine composed of cultured tumor-responsive macrophages. It gives me the creeps to realize that after all this intensive intervention in glycopathology, some cancer stem cells still survive and find another path to lethality. So as crude as it sounds, it seems that a kitchen sink approach is necessary, especially when faced with metastatic cancer. And that doesn't depend on us having an Elysium scanner.
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#17 pone11
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 05:14 PM seivtcho, on 20 Jan 2015 - 02:59 AM, said: By the way, aren't this thing about the mitochondria and the cancer off-topic for mitochondria transplants? Why not you make another topic for that? Mag1, do you want to start a new thread and then point us there? Do you want the administrator to move the discussion out of this thread into that one?
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#18 mag1
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 05:42 PM Sure, if this goes on much more we probably should start another thread. First, I will wait for the eviction notice.
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Point taken about the journal articles. They are not from the top tier of the journal list. It is a concern, when obscure journals publish such sensational results. However, the original research was published over 10 years ago from Johns Hopkins. The animal results they reported for animals were equally stunning. The FDA has granted 3BrP 2 orphan designations and authorized a human trial to start almost 2 years ago.

It is surprising and disheartening how the US handled the 3BrP find. The investigator who discovered it was fired and has had to enter litigation to receive due recognition for the work. It appears that the university has appropriated the discovery and is developing it as if they discovered it.

Notably, the Columbians are including salinomycin with 3BrP as a combination treatment. Salinomycin has attracted considerable interest in its own right as it appears to have potent anti-cancer stem properties. There have been published human reports demonstrating its effectiveness in cancer therapy.
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#19 pone11
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 05:46 PM mag1, on 20 Jan 2015 - 6:42 PM, said: Sure, if this goes on much more we probably should start another thread. First, I will wait for the eviction notice.
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Point taken about the journal articles. They are not from the top tier of the journal list. It is a concern, when obscure journals publish such sensational results. However, the original research was published over 10 years ago from Johns Hopkins. The animal results they reported for animals were equally stunning. The FDA has granted 3BrP 2 orphan designations and authorized a human trial to start almost 2 years ago.

It is surprising and disheartening how the US handled the 3BrP find. The investigator who discovered it was fired and has had to enter litigation to receive due recognition for the work. It appears that the university has appropriated the discovery and is developing it as if they discovered it.

Notably, the Columbians are including salinomycin with 3BrP as a combination treatment. Salinomycin has attracted considerable interest in its own right as it appears to have potent anti-cancer stem properties. There have been published human reports demonstrating its effectiveness in cancer therapy. I think this is an important thread that should continue to evolve for years on this site. It deserves a new topic of its own so that the discussion can continue.

The two URLs you posted are not scientific journals at all. They are advertisements for alternative cancer cure clinics. Profit motive here may overshadow the science.
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#20 mag1
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 05:48 PM http://www.ncbi.nlm....les/PMC3516046/*Quote
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#21 mag1
<p class="posted_info desc lighter ipsType_small">Posted 20 January 2015 - 05:59 PM Sorry for the confusion.
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The 2 articles I referenced above were:

A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr. 2012 Feb;44(1):163-70. doi: 10.1007/s10863-012-9417-4. Epub 2012 Feb 11.

Chin J Cancer. 2014 Jul;33(7):356-64. doi: 10.5732/cjc.013.10111. Epub 2014 Mar 14. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study

It is true that the 2 urls that I provided were for profit cancer clinics. However, the American clinic has been granted government authorization to provide 3BrP treatment. Such approval would likely require some regulatory oversight. It also highlights the fact that 3BrP has probably been administered to human cancer patients in a high quality medical environment and such treatment, under those circumstances, is safe.
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#22 mag1
<p class="posted_info desc lighter ipsType_small">Posted 24 January 2015 - 05:44 PM A new method of delivery for 3-Bromopyruvate could enhance its effectiveness.
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Clin Cancer Res. 2014 Dec 15;20(24):6406-17. doi: 10.1158/1078-0432.CCR-14-1271. Epub 2014 Oct 17. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer.

http://www.ncbi.nlm....les/PMC4300523/
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#23 YOLF
<p class="posted_info desc lighter ipsType_small">Posted 24 January 2015 - 09:00 PM <span style="font-size:14.3999996185303px;color:rgb(255,0,0)">Moderation  - I've moved some posts from a similar discussion  here. The title has also been modified to reflect the additions.
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Edited by PerC, 24 January 2015 - 09:08 PM.


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#24 mag1
<p class="posted_info desc lighter ipsType_small">Posted 24 January 2015 - 10:17 PM I am not sure about the reorganization of this thread. This thread never gained much traction, so I decided to hitch a ride on another thread and report on the 3-BP story there.
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This thread might still not generate the right vibe to attract a following.
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#25 YOLF
<p class="posted_info desc lighter ipsType_small">Posted 25 January 2015 - 03:14 PM What do you suggest?
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#26 mag1
<p class="posted_info desc lighter ipsType_small">Posted 25 January 2015 - 05:10 PM I do not think that I would have moved the 3-BP items from the Mitochondrial thread here.
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In the Mitochondrial thread, I wanted to point out the effectiveness of 3-BP: that was accomplished. A learning opportunity emerged when the actual therapeutic result from the

article in Chin J Cancer. 2014 Jul;33(7):356-64 was misunderstood. Two treatments of 3-Brp and salinomycin resulted in a therapeutic cure for a patient with terminal cancer!

It was noted on that thread that 3-BP is an important subject for this forum to address over the next few years. After accomplishing my objective, I intended that the Mitochondrial thread could revert back to its main topic. Unfortunately, the 3-BP comments on that thread sapped the enthusiasm of others and it has now become inactive. I did not intend that to happen.

Sometimes a bit of heated disagreement is required to give life to a conversation. This 3-BP thread has been unable to generate such energy, even though 3BP is possibly an important development in cancer treatment. 3-BP could be the cure for cancer. The lackluster success of this thread encouraged me to catch a wave on another thread and push the 3-BP message there.

A sensationalistic thread topic such as: <span style="color:rgb(255,0,0)"><span style="font-family:tahoma, geneva, sans-serif">Is 3-Bromopyruavte the cure for cancer? might help. However, I do not want to overstate the evidence.
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#27 pone11
<p class="posted_info desc lighter ipsType_small">Posted 27 January 2015 - 06:42 PM PerC, on 25 Jan 2015 - 4:14 PM, said: What do you suggest? Using 3-Bromopyruvate (3-BP) to Fight Cancer Is 3-Bromopyruvate (3-BP) a Cancer Cure?
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mag1, on 24 Jan 2015 - 11:17 PM, said: I am not sure about the reorganization of this thread. This thread never gained much traction, so I decided to hitch a ride on another thread and report on the 3-BP story there.

This thread might still not generate the right vibe to attract a following. So what is the other thread in which you want to post 3-BP information?

Why not fix what you think is broken in this thread rather than taking another thread off topic?
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#28 resveratrol_guy
<p class="posted_info desc lighter ipsType_small">Posted 01 February 2015 - 03:08 PM So when I read about the Alzheimer's side effect above (which is probably an exaggeration, as 3BP was directly injected into the CNS, which would never happen except perhaps for brain or spine cancer), I nonetheless am reminded of the purportedly anticancer agent graviola (also known as soursop and in the same plant family as paw paw, another rumored cancer killer). (BTW a family friend had metastatic liver cancer a few years ago -- after being cured of colon cancer via conventional medicine -- and has been in remission ever since, apparently due to a regimen of paw paw along with a Gerson-ish diet and other therapies.) But my point here is the neurotoxicity issue: graviola can also be neurotoxic (depending on the particular dose of seed or fruit extract). This suggests to me that graviola and 3BP might be acting on related pathways, in which case, the former might be a cheaper and more accessible alternative in desperate situations. This is also unsurprising, given the recent studies (for example) demonstrating a significant anticorrelation between cancer and Alzheimer's.
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So as I understand it, plain vanilla IV 3BP is basically useless; one needs paracetamol to lower the glutathione antioxidant defense of the tumor cells in order to make it effective. (Organ-targetted 3BP-only therapy is potententially effective, but the delivery mechanics are obviously nontrivial, so IMO this is an impractical approach.) So it kind of sounds like 3BP causes HK2 to indirectly downregulate glycolysis. Then, robbed of half their energy, normal oxidative stress becomes an overwhelming tax on the cancer cells which are also glutathione depleted, resulting in cell death. (Not to forget salinomycin, but I'm no expert on it.) Somehow, during this process, we need to preferentially protect healthy cells. Perhaps a proapoptic agent which is also an antioxidant, such as reveratrol or pterostilbene, would be useful. c60oo (and similarly, nicotinamide riboside) might be useful as well, judging from the original Baati experiment, although it's not completely clear whether or not it would protect cancer once it had already developed, even though it appears to prevent it in the first place. (Here is one early encouraging result.) Anyway, I'm just trying to think of a way to protect the patient from undue oxidative and neurological stress (nicotine? lithium? NGF eye drops?) while we fry the cancer. This isn't idle fascination; a friend of a friend of mine (not the guy above) has metastatic pancreatic cancer. I've told his wife about 3BP, for starters.

A ketogenic diet has obvious benefits, but is unpalatable to some people, even some people with cancer. (And with digestive cancers, the fat load would require increased synthetic enzyme intake, if it could be tolerated at all.)

[Mods: IMO this is "the" 3BP thread, based on internal search ranking, so I vote to keep it that way.]

Edited by resveratrol_guy, 01 February 2015 - 03:38 PM.


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#29 mag1
<p class="posted_info desc lighter ipsType_small">Posted 01 February 2015 - 03:18 PM Thanks. I am liking this is THE 3-BP thread.
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I want to generate a positive vibe so that all the cool people will join in. The problem with this forum is that there is no good way to filter down all the bogus cancer threads so that ones like 3-BP are more prominent.

Longecity does not have many hard core cancer patients posting, so the threads do not have the same urgency as elsewhere. Check out some of the latest posts from the cancercompass forum. http://www.cancercom...all,65701,0.htm
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Advert:Advertise on LongeCity===#30 resveratrol_guy=== <p class="posted_info desc lighter ipsType_small">Posted 01 February 2015 - 03:34 PM
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mag1, on 01 Feb 2015 - 4:18 PM, said: Longecity does not have many hard core cancer patients posting, so the threads do not have the same urgency as elsewhere. Check out some of the latest posts from the cancercompass forum. http://www.cancercom...all,65701,0.htm We have the biohackers. They have the desperate patients. So to anyone with an established reputation on a patient site, I would recommend making a few polite posts, inviting cancer patients (or better yet, their healthy family members who are not mentally drained by the disease) to visit Longecity cancer threads such as this and others. There is no excuse for keeping the public in the dark about potentially powerful (albeit lightly tested) alternatives, but by and large, that's just the way things work by default. Thanks to you and others for sharing this information.

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175 replies to this topic ===							 #31					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 01 February 2015 - 03:47 PM

resveratrol_guy, on 01 Feb 2015 - 4:08 PM, said:

The way I read the original research that I responded to, cancer upregulates the HK2 enzyme, and it uses this to increase glucose going into the damaged mitochondria that are stuck in glycolysis. The primary mechanism that explains the success of 3BP is that it downregulates HK2 in all cells. But because cancer cells are the only ones that rely on HK2 heavily for glycolysis, this ends up being a method of attack that is preferential against cancer. Downregulating HK2 in a normal cell will not kill it.

It was not clear to me that you had to have paracetamol for the effect to take place. Did you find any in vitro studies where 3BP alone did not work, but 3BP + paracetamol did?

Ketogenic diet should be an additive therapy here, as would be any other pro-oxidative therapy. Dominic D'Agostino's research shows the added benefits of hyperbaric oxygen. As a pure speculation, I am guessing that ozone injection (as practiced by Dr Shallenberger in Nevada) might have a positive effect as well, since it tends to flood the cell with oxygen and create a cascade of events that increase the NAD+/NADH ratio and speeds up aerobic metabolism.

One of the most intriguing parts of Dominic's research is his finding that a ketone ester will put a mouse into a chemically induced ketosis for hours. The esters are too expensive at this point to make commercially, but it suggests that at some point in the future it might be possible to buy an ester and spend much of the day in ketosis without the pain of a ketogenic diet. *							Report ===							 #32					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 01 February 2015 - 03:51 PM
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mag1, on 01 Feb 2015 - 4:18 PM, said:

The best way to get attention on Longecity is to generate traffic in the thread. You might want to cross post significant new posts in that other thread.

You don't want urgency. You want respect for good science and the truth. Forums with desperate patients tend to just give a thumbs up for every idea including bad ones.

Have you found any new human trials of 3BP conducted within peer review research of an academic institution, not by a for-profit cancer clinic? Edited by pone11, 01 February 2015 - 03:52 PM. *                               						*							Report ===						sponsored ad					=== *			Advert Advert:
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Posted 01 February 2015 - 04:57 PM

pone11, on 01 Feb 2015 - 4:47 PM, said:

Maybe it's an overstatement to say that paracetamol is necessary to potentiate the benefits of IV 3BP. But then again, is there any good reason not to use it, because it's a well-understood and low-risk drug if we're talking about short term moderate doses? Temporary glutathione suppression should not be an issue, if only we can preferentially protect the normal cells.

I do recall D'Agostino mentioning that hyperbaric oxygen is anticancer (most likely due to favoring OXPHOS over glycolysis), but in the same video, he showed images of cell membrane damage resulting from the therapy. Damaged membranes might increase the risk of cancer in the long term. So I would think the ketogenic approach (especially the "ketodrinks" that you mentioned) would be safer. (Hopefully a less regulated marketplace will spur mass-production soon, so the product will be cheap the second that the research is done.)

However, despite the apparent promise of 3BP and antiglycolysis in general, I think the opposite approach is worth considering: demotivate the cancer by putting it on welfare, wherein it becomes addicted to chemotherapy to the detriment of its aggressive capacity. *							Report ===							 #34					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 01 February 2015 - 06:32 PM
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The article with the patient with metastatic melanoma showed a fairly modest response when given 8 doses of 3-BP at the recommended dose. However, two combination doses of 3-BP and paracetamol cured the cancer! (see figure 3 from the below url).

http://www.ncbi.nlm....les/PMC4110469/

The other published human 3-BP patient report noted a very large anti-tumor response to straight 3-BP though at a higher dose than in the above report.

http://www.ncbi.nlm....pubmed/22382780

It should be pointed out that paracetamol is nothing more than acetaminophen. We had a bottle of it lying around and did not even know that this was paracetamol. Is a prescription even required for it?

The readers of this thread are a hard bunch to impress. The cancer compass url that I gave in a earlier post, mentioned that minicell treated mice required a 25,000 times (or greater) reduction in chemotherapy while still achieving curative responses. In one noted report mice were cured of cancer using 4 time weekly dosing of 520 ng! I was stunned by these results. Wasn't anyone else?

With minicells, it does not really matter that much what anti-cancer drug is loaded into minicells. Yet, loading minicells with 3-BP, paracetamol and salinomycin might produce interesting results. *							Report ===							 #35					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 01 February 2015 - 06:51 PM
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The only two accessible published patient reports in humans of 3-BP are noted in my last post.

It is disgraceful that so many years after the original research was published there is almost no human experience with 3-BP. This extraordinary ignorance puts patients in a very difficult position. If they try the drug with the present minimal information regarding its use in humans they might regret it. The patients reports chosen likely reflect strong positive publication bias. What were the results with other patients who the authors of the papers might also have treated. Should not these details be included in the journal articles? However, given the limited choices presented to many cancer patients, many might feel that 3-BP is there best chance.

I strongly believe that the outcomes in treating patients with 3-BP and other alternative treatments should be required by law to be published. A simple online journal of such reports would be invaluable in helping patients make the best treatment choices.

It has been reported that the Columbian clinic has published a positive report using 3-BP and salinomycin in lung cancer. However, it does not appear to be on pubmed yet. 3-BP is also being used clinically in Germany, though no published reports. The Dayspring clinic has been granted the right to treat with 3-BP, though it is not clear whether anyone has actually received 3-BP treatment from them. The initiation of the American phase 1 trial for 3-BP which was authorized to begin immediate enrolment almost 2 years ago is now being pushed further into 2015 (perhaps the spring). Edited by mag1, 01 February 2015 - 06:52 PM. * Quote *							Report ===							 #36					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 01 February 2015 - 07:34 PM
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mag1, on 01 Feb 2015 - 7:32 PM, said:

Be careful about Figure 3. Figure 3 does not show cancer as cured. Figure 3 shows that LDH went to near-zero levels after the treatments. LDH is a metabolite that is often a good marker for cancer progression. What was that patient's final outcome? If there were skin cancers that had metastasized why didn't they biopsy the tumor and try to show explicit regression of an established tumor? It's a waste of such a good outcome for them to not go further than measuring a metabolite.

Since you are seriously ambitious about pursuing 3BP, can I suggest you contact the main researchers on that study and ask them about that, and then also ask them about future human trials they are conducting, as well as other groups they know about?

I missed the study on minicells, can you repost the link and summarize what these are and how they work?

What I like about Longecity is that the readers approach EVERY claim with a similar skepticism that a scientist might show, and they evaluate evidence critically. That's a good thing, because it keeps people sharp and it keeps conversations focused on science. On nearly every other health forum I visit, people who cannot read or understand science just throw emotions at each other. Claims with little proof are easily believed, and claims with fantastic proof are easily dismissed. I agree with you this is a hard place to make a point, but generally I find the dynamic much healthier, and people do not waste time on silly claims. Edited by pone11, 01 February 2015 - 07:37 PM. *                               						*							Report ===							 #37					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 01 February 2015 - 09:47 PM
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From the article regarding the patient with metastatic melanoma"

"Serum LDH, a good parameter for the evaluation of tumors such as melanoma, is  superior to the presence of a residual tumor mass for predicting treatment outcome

... Interestingly, serum LDH level reflects metabolic energy activity of cancer cells inside tumor mass, which may be a more sensitive indicator of tumor activity than tumor size.

... When discussing anticancer effects of 3BP, serum LDH level estimation as a response to treatment is critical, as 3BP is a structural analog of both lactate and pyruvate. Lactate produced through activity of LDH fuels aerobic populations inside tumors via metabolic symbiosis."

The authors are stressing the point that mere tumor burden at death in this patient report is not as relevant as the fact that the tumor mass had lost almost all viability. I am not entirely sure, though it seems quite possible that a tumor mass that had lost its ability to produce lactate is essential destroyed. LDH a widely used biomarker for tumor burden.

It should be emphasized that the near elimination of LDH occurred after only 2 combination treatments.

The below url nicely summarizes 3-BP research. It provides some background on a third successful human patient treated with 3-BP, though no journal reference is given.

https://www.dropbox....view_A.pdf?dl=0

The cancer compass url I posted earlier goes through all the details of minicells treatment. One of the members of the thread is trying to arrange minicell treatment. As you read through the posts (these posts are the recent ones), it turns out that minicell treatment poses surprisingly few obstacles to those with some lab background.

The below url provides a good introduction to minicells. On page 5 of the article, (Figure 1A) notice that 520 nanograms of monastrol 4 times per week loaded onto minicells cured the mice of cancer! NANOGRAMS! A weekly dose of 125,000 ng of free monastrol had almost no effect on slowing tumor volume. Such small doses even below the scale of homeopathy are possible because the minicells specifically target cancer cells.

http://www.tandfonli...61/cc.6.17.4648

Cell Cycle. 2007 Sep 1;6(17):2099-105. Epub 2007 Jun 27. Bacterially-derived nanocells for tumor-targeted delivery of chemotherapeutics and cell cycle inhibitors.

The one emotion that I might throw around on this forum regarding 3-BP is exasperation. How could treating seriously ill cancer patients with drugs that have often proven ineffective be considered ethical when the results from 3-BP appear quite impressive? *							Report ===							 #38					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 01 February 2015 - 11:39 PM
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mag1, on 01 Feb 2015 - 10:47 PM, said:

All clear, and the question still is why didn't they report the tumor mass. It's an odd thing to say that the metabolite better predicts outcome but then not show the outcome.

mag1, on 01 Feb 2015 - 10:47 PM, said:

The one thing I would point out on the study that combines 3BP and Paracetamol is that the data is not as conclusive as you think. With 3BP alone the LDH levels appear to be in steady decline, and then only at about 20 days into the study do they introduce Paracetamol. That really spoils the data. They should have had two separate test groups, one with 3BP only, and one with the two drugs combined from the start. I only read the charts, so maybe I am missing something?

mag1, on 01 Feb 2015 - 10:47 PM, said:

The minicell approach looks wrong for delivery of 3BP. The entire point of 3BP is that it exploits the fact that cancer cells have these elevated HK2 levels and more pathways into the cell and mitochondria both for delivery of glucose. 3BP is selectively targeting cancer cells by riding through those gateways into the cell. What possible reason would there be to use minicells? The whole point of 3BP is that normal cells won't uptake enough of it to kill their energy metabolism, but cancer cells will. You don't get added benefit through minicells? People should just focus on getting real trials with humans done with 3BP, not wasting time on new science. No new science is required to just test what already exists and seems to work well.

Morever, minicells as they are described are just a package. They are not the trick used to deliver the package, and that is the hard part of the problem. Each cancer has a different way of altering the cell membrane, and you have to figure out what that is *for each type and variation of cancer* and how to use that membrane structure in order to deliver the minicell. That's what cancer scientists have been trying to do for the last 30 years and largely falling on their faces in failure. Many times they develop a drug that selectively delivers into a cancer cell, the cancer cell then evolves over time to overcome that architecture. What makes 3BP unique is that it appears to be utilizing the primary energy pathway for the cancer cell, which the cancer cell cannot evolve away without changing its whole metabolic approach.

Maybe I am not understanding something about how minicells get delivered?

mag1, on 01 Feb 2015 - 10:47 PM, said:

Well, it did not help that the researcher who originally discovered 3BP is claiming it as his proprietary discovery. Many might have been scared away because of threats of litigation.

The system is also very broken because research money is available for proprietary drugs or things that can be turned into proprietary drugs. It could be that some see 3BP as free and therefore not something that can be made proprietary. And those who see it as proprietary are leaving it to the researcher who claims this to get his own funding.

If you really care about this, why not contact the researchers of the study you post, as I suggested? They might know of other human trials and you could start to track those. They might also have a perspective on why more groups are not jumping on this. I already posted about Dominic D'Agostino's group in Florida, and they want to test a different HK2 inhibitor similar in action to 3BP. They cannot get funding, even though they already have very impressive in vitro results. The system is corrupt. It's not about pure science. It's about groups with money finding ways to make money for themselves, and sometimes it is about not funding things that you think might hurt your other interests. Edited by pone11, 01 February 2015 - 11:55 PM. *                               						*							Report ===							 #39					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 02 February 2015 - 12:15 AM
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The tumor mass itself did not seem relevant to them. It was just a large mass of destroyed tumor cells. LDH is a traditional method to determine whether a determine is actually active. In the 2012 patient report, they noted that none of the cancer cells they found in the patient were viable. There was just liters of fluid of destroyed liver cancer cells.

The authors consider the decline in 3-BP from over 4000 to 1800 with single 3-BP treatment to be "minimal"

"After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level.

...Maximum LDH decrease upon combined treatment confirmed that tumoral GSH was antagonistic to 3BP-induced melanoma cell death. That might indicate a shut down in glycolysis in melanoma cells and signal metabolic cure of metastatic melanoma."

They already knew that 3-BP was not likely to be as effective as a combination would be. They go on to note that previous research had found that 3-BP alone was not sufficient to effectively treat melanoma. It had been found that a GSH depleotr would be needed (e.g. paracetamol).

The minicells allow for dramatic reduction in dosage, the combination with a variety of other medications, and direct targeting to cancer cells. The research has noted that some cancer are resistant to 3-BP treatment because they lack MCT receptors. A cancer would likely never be able to withstand being subjected to 3-BP if it gained entry into the cell. Minicells provide this opportunity because any cancer receptor can be added to the surface of the minicell. There are many receptors to choose from. The bi-specific antibodies on the minicells could be changed and the cancer cell would have no way to defend itself. Cancer cell can shut off entry via MCTs.

The suspicion would be that pharmaceutical companies are working overtime trying to find a better and patentable form of 3-BP. It is possible that they have not been able to accomplish this. Possibly the molecule needs to be as simple as 3-BP to work and perhaps this means that there is a problem making the drug different enough from 3-BP to file a valid patent.

I would be inclined to watch the 3-BP story develop from the sidelines. *							Report ===							 #40					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 02 February 2015 - 01:15 AM
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mag1, on 02 Feb 2015 - 01:15 AM, said:

Good science requires good experiments. Changing a protocol mid-stream isn't the way you do it in order to record the purest result.

I'm not saying that 3BP is not effective. I'm not saying the combination therapy wasn't better. I'm saying the way they reported it is not great science.

mag1, on 02 Feb 2015 - 01:15 AM, said:

The value of minicells is to deliver massive doses of toxic chemicals in a targeted way, just into cancer cells. 3BP does not need this. They can already get a toxic dose selectively into just cancer cells. Moreover, the presence of 3BP outside of normal cells does not appear to be toxic to those cells. Therefore there is no need to avoid a systemic toxicity with 3BP in the current dosing regimens.

If you had a minicell, what is the mechanism for getting it into the cell? The answer to that would be different for different types of cancers. Why introduce a new problem you didn't have with 3BP alone? Minicells appears to solve a problem that doesn't need to be solved, relative to this particular therapy 3BP.

I contacted the researchers on both of the 3BP studies you posted today. We'll see if they have any information on new studies or on reasons for slow uptake by other researchers. *							Report ===							 #41					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 02 February 2015 - 06:37 PM
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I am very glad that they did not put science before their ethical obligations. These researchers were able to clearly show that straight 3-BP had a fairly modest effect on the patient's LDH level after several treatments at the given dosage level. They then showed that paracetamol in combination with 3-BP had a very profound and immediate effect on LDH levels after 2 treatments. Science in general (and 3-BP treatment in particular) would be much further advanced if such a more practical (adaptive and moral) scientific approach were used in research. Adaptive designs merely respond to circumstances as they arise. There is no compelling argument to be made that experiments must rigidly continue with an hypothesis that has been shown to be invalid. 3-BP alone was not shown to be overly effective as a single agent at the dosage used in the patient report. There was research that suggested paracetamol would increase its effectiveness. When they did the combination, the result was a much more effective treatment.

The minicells deliver nanoscale doses directly to cancer cells. 3-BP will only be effective in cancer cells that express MCTs. Not all cancer cells do. Cancer has always had an infuriating ability to become resistant to any treatment. This is why cancer has yet to be cured. If even a single cancer cell becomes resistant to a treatment, then there will be a recurrence. Minicells might get around this problem by allowing 3-BP to enter any cancer cell (even those cancer cells without MCTs). As has been pointed out on this thread, cancer cells likely would not be able to change their primary method of energy metabolism.

Minicells might appear to be a side-issue until it is noted that the patients reported in the published reports had massive responses and were likely selected for publication because of these overwhelming responses. Patients with different patterns of MCT receptor expression might display much less favourable responses to 3-BP treatment. The publication of such disappointing results might hold back 3-BP for many years while the reasons behind such disappointments were investigated.

3-BP is a strong candidate for preventative cancer management. 3-BP enclosed in minicells might allow miniscule doses of the drug to completely prevent the emergence of cancer. It might not be considered ethical or be shown to be effective if it were to be given systemically. *							Report ===							 #42					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 02 February 2015 - 11:15 PM
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mag1, on 02 Feb 2015 - 7:37 PM, said:

I saw one researcher claim that 3BP might treat 95% of all cancers. How about we get the drug tested for those 95% and worry about the 5% later? It's not like there is a flood of 3BP research in humans and we have the resources to dilute that research in so many directions.

I still think you don't seem to understand that most of the 3BP is already going into the cancer cell, and it is staying out of the normal cells. If a drug does not threaten normal cells, and most of it goes into the target cancer cell, what added benefit do you get from minicell encapsulation? You keep trying to solve a problem that doesn't need to be solved, for this drug.

Contrast that to one of the many lethal toxins that are used in chemotherapy. These drugs kill healthy cells, not just cancer cells. For such a drug, there is a huge benefit to the minicell, as a  way to release the toxic payload only inside of a cancer cell. We don't have that problem for 3BP, and your approach doesn't improve effectiveness of 3BP in the cancer cell. It's not clear what problem you want to solve. *							Report ===							 #43					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 02 February 2015 - 11:15 PM
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I'm not sure how much of a cure this was, since the guy died from a cardiac metastatic lesion, leading to hypoxemia. He was reported to have died 12 Oct 2012. Maybe if they had started the treatment earlier, and started the acetaminophen at the same time it might have turned out differently. *							Report ===							 #44					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 12:04 AM
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The patients selected in the published reports were patients that medicine had nothing left to offer. In both instances the responses the patients had to 3-BP treatment was extreme.

The German report of liver cancer was extraordinary. The boy would have been offered the best possible options for his treatment. These options showed dim prospects of success using standard treatment. The ethics committee carefully deliberated what should be done. When the decision of the committee was decided in favor of allowing 3-BP treatment, treatment began immediately. There were no side effects. How many chemotherapy patients could say that? When they gave another dose, there were still no immediate side-effects, though later that day the boy went into a coma because there had been an overwhelmingly massive destruction of cancer cells (Tumor lysis syndrome). It is not entirely clear how the doctors had not anticipated such an outcome or why the ethics panel did not require monitoring for such a likely side-effect.

The question that springs to mind is why are not all end stage cancer patients demanding this treatment? Over half a million cancer deaths are expected in America this year! It will not take many more published reports similar to the one from Germany before there is a rush by desperate end stage cancer patients to try it.

The metastatic melanoma patient also had a hopelessly severe cancer burden. It is not difficult to imagine how a conventional oncologist might react if such a patient were thrust unto the doctor for care. Such a patient would have few possible treatment options. The article notes that the patient had run out of treatment choices. This patient also experienced no side effects from treatment and was standing comfortably after his treatments. Dismissing the metabolic cure of the patient with combination 3-BP and peracetamol treatment seems unreasonable. It is not hard to imagine that such a patient could have been saved if a surgical intervention had restored his ability to breathe. Edited by mag1, 03 February 2015 - 12:06 AM. * Quote *							Report ===							 #45					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 12:29 AM
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The 95% figure for the cancers that 3-BP could treat actually represents 100% of active cancer. The 5% figure given for cancers that could not be treated by 3-BP are those cancers that are metabolically inactive. Such cancers would not be aggressive or possibly even life threatening.

It should be further noted that in neither of the published reports with 3-BP did the patients actually succumb to cancer even though the illness burden was overwhelming. The metastatic melanoma patient succumbed to hypoxemia and the liver cancer patient succumbed to liver failure. The liver cancer patient had liters of fluid filled with cancer cells. None of the cancer cells were found to be viable. *							Report ===							 #46					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 03 February 2015 - 01:32 AM
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mag1, on 03 Feb 2015 - 01:04 AM, said:

I can't remember which thread mentioned it, but there are new laws sweeping through the US state legislatures now that make it legal for a patient with a terminal illness to seek treatments that the FDA has NOT approved. That's an incredibly important step, but as the sad cases above make clear, when a patient allows the cancer to get too far, the cure can be as bad as the disease. That's no fault of 3BP I guess, and they just need to get experience in not killing too much cancer too quickly. I think that is a good problem to have probably, if the alternative is a therapy that barely stops the growth of the cancer.

Let's hope that patient demand alone forces researchers to start to take 3BP more seriously.

If you had cancer, I wonder if you wouldn't prefer 3BP as the first line treatment. Getting that to happen would be tough.

As an aside, have any of the animal studies looked at using 3BP to treat primary brain cancers? Does 3BP easily cross the blood brain barrier? mag1, on 03 Feb 2015 - 01:29 AM, said:

Okay, so no need for minicells here! And that is great news, because 3BP by itself might be both safe and effective for a wide array of cancers! *							Report ===							 #47					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 03 February 2015 - 04:42 PM

pone11, on 03 Feb 2015 - 02:32 AM, said:

3BP might work with brain tumors, with a little help: "C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes".

https://www.ncbi.nlm...pubmed/21921941

Obviously there's the Alzheimer's risk to consider as well, if there's any human reality to it. But better that, than glioma.

But let's be honest about this: there are no pharmabucks in 3BP, especially after the patent fiasco, so the odds of getting a clinical trial concluded and published (like the interminably delayed one mentioned above) is essentially zip. And how would you test something this broad, anyway? One cancer at a time, until the next Ice Age?

If 3BP is in any way true to its hype, it will be tested by individuals in desperate situations, at Dayspring or other clinics like the Colombian one. The accumulation of dirty data that comes from those trials-of-one will far outweigh the value of any particular nonhappening "good science" trial with no funding and no route to profits. Obviously patients need to be informed that this substance is still stuck in the lab, but they deserve the choice.

And seriously, we're not talking about finding the boiling point of water here. The data analysis required to do good science, even over the course of decades, would be overwhelming. (And then the nerds would pick it apart with "poorly constructed trial" etc. etc. forever.) The dirty data approach will be faster, and ultimately, save more lives and provide more information. Even if 3BP "only" raises 5-year survival for pancreatic cancer to 10%, that would be a Nobel Prize level accomplishment. OTOH if it's all hot air, then I think that would become rapidly obvious through crowd reporting, probably before this pseudotrial even kicks off. At least, in that case, we'll be off to the next drug candidate while the FDA is still sharpening its pencils.

The reality is probably that 3BP needs assistance from other compounds, along the lines of minicell therapy or the article above. But that's optimization. Let's take what we can get and allow people to try to fix their life-threatening problems. (This goes to the "Right to Try" legislation alluded to above. Right to Try is complicated like any piece of American legislation, but there are certainly elements in it that make good ethical sense.)

I'm not against good science. It's just that biology is too complicated, and cancer moves too quickly. It is no understatement to say that every cancer is a computer trying to solve a molecular problem. It has a gun to your head, and as soon as it figures out how to pull the trigger, it could kill you. Are you going to sit there trying to figure out how the gun works, or start attacking it with everything you have, learning what you can from others who have fought off similar attackers? Edited by resveratrol_guy, 03 February 2015 - 04:42 PM. *                               						*							Report ===							 #48					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 03 February 2015 - 06:35 PM
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resveratrol_guy, on 03 Feb 2015 - 5:42 PM, said:

Here is full text for the rat brain cancer study you linked:

http://www.nature.co...cgt201159a.html

How weird that they did not do a lifespan result in that experiment. I get the feeling they treated the rats for a short time and then just killed them to get their data. What a loss to not understand the real effects of the treatment on the overall course of the disease....

I'm all for dirty data. Right to try laws should help researchers who want to conduct such trials to not need approval from the FDA. That's really important to streamlining the process. *							Report ===							 #49					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 06:41 PM
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Tumor Lysis Syndrome is a completely preventable and treatable medical condition. (For example, Prophylactic allopurinol can be prescribed to patients. Kayexalate can be prescribed to reduce serum potassium levels. etc.)

Minicells might help, though, in avoiding this problem altogether. When giving straight 3BP, there is a real sense that you are riding on a lion. The dosing curves showed that 3-BP has no measurable effect on cancer at small enough doses, though once the therapeutic effect of 3-BP begins there is a rapid dose response. This problem might still need to be worked through, in order that 3-BP could be given safely. Consider that if the metastatic melanoma patient had lived his entire tumor mass had been destroyed. A Tumor lysis response under such conditions would not be unexpected.

However, consider how minicells might help avoid the tumor lysis problem. A minicell with 1 million or more drug molecules certainly would destroy a cancer cell once it gained entry. There would therefore be a linear response over the entire range of therapeutic dosing. It would, thus, be easy to avoid a tumor lysis response with minicells. This is illustrated in Figure 1A from http://www.tandfonli...61/cc.6.17.4648. The dosing in the mice showed how easy it is with minicells to control the cancer elimination process. *							Report ===							 #50					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 07:00 PM
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Does anyone know how to change the tags on this thread? I am not sure whether this can be done once the thread has been created.

I would like to add the tag "The cure for cancer". So many of the other cancer topics are really not related to curing truly extreme levels of metastatic illness as 3-BP has shown itself capable of. I would like to see whether any other therapeutic with a cancer cure tag could match 3-BP. Perhaps minicells? Car T-cells? Let's throw down the gauntlet and see who steps up.

Changing the tag could really help focus attention on the astonishing anti-cancer properties that have been demonstrated by 3-BP. Most of the other threads with the cancer tag do not appear to offer curative responses for those with severe metastatic illness. I eat my fruits and vegetables and I highly recommend them to others reading this thread. It's just that I do not think they would cure someone with severe metastatic cancer. *							Report ===							 #51					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 03 February 2015 - 08:33 PM
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mag1, on 03 Feb 2015 - 7:41 PM, said:

The very first sentence of the abstract from the study you link is: "Chemotherapeutic drug therapy in cancer is seriously hampered by severe toxicity primarily due to indiscriminate drug distribution and consequent collateral damage to normal cells."

Minicells are about preventing collateral damage to NORMAL cells. They don't change the nature of the death for the cancer cell. Dead is dead. ANY therapy that kills a large enough number of cancer cells at one moment is going to create a tumor lysis problem.

Anyone delivering these 3BP therapies is going to need to become extremely expert at managing tumor lysis. It's about delivering just enough of a dose to kill cancers, and then every few hours monitoring the blood for the byproducts of those dead cells. Once that lysis heads back down, they can then redose 3BP. But does a significant gap between 3BP doses allow the cancer cells to reestablish? How tricky is it in practice to dance between death by living cancer and death by dying cancer?

This is why I can't help but wonder if these 3BP treatments wouldn't have the most value right at the start of cancer treatment, rather than waiting for terminal condition. But getting permission to use 3BP when you are not yet "terminal" might be tough? *							Report ===							 #52					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 08:57 PM
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The point to focus on is that minicells can be dosed in a precise way to destroy exactly the number of cancer cells that would be safe in avoiding tumor lysis syndrome but yet still highly effective.

Consider this. When you inject 100 minicells loaded with 1 million drug particles into someone with cancer, 30 cancer cells might be destroyed (as per the results of one of the published studies). If you increase the dose 1000 fold to 100,000 minicells you will destroy 30,000 cancer cells. If you increase the dose a further 1000 fold to 100,000,000 (10^10 was the maximum tolerated dose in the human phase 1 trial) minicells, then you will destroy 30,000,000 cancer cells. The number of cancer cells destroyed is completely proportional to minicell dose. Finding the safe dosing range to avoid tumor lysis syndrome would be easy. The number of cancer cells that would create a risk of tumor lysis syndrome is likely a widely known quantity. The mouse study that I referenced in my last post showed how easy it was to use minicells to induce a safe gradual reduction in tumour volumes.

However, injecting straight 3-BP dose not have such a clear linear relationship between dose and cancer cell destruction. Over much of the low end of the dosing range, it does not appear that 3-BP has any appreciable influence on cell survival. A certain minimum threshold of molar dose needs to be reached before 3-BP becomes effective. It seems a more difficult task to precisely determine how many cancer cells will be destroyed for a given dosage of 3-BP. Two doses of paracetamol with 3-BP in the one patient report example resulted in an extreme response. Straight 3-BP appears to be a powerful yet currently somewhat unpredictable treatment. It will likely not require extensive experience with it to figure out the correct dosing, though it does highlight the dangers that could arise from treatment by the do it yourselfers. *							Report ===							 #53					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 09:40 PM
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It is particularly interesting to reread the patient report from Germany. It does not seem outrageous to suggest that the patient's ultimate demise might be related to tumor lysis syndrome. Figure 3 show that after the 10th 3-BP treatment the patient experienced the highest level of urea noted in the figure.

From the article "About 1 l of ascites fluid was removed and sent to the pathology lab for cellular analysis. ... This lack of tumor cells in the ascites suggested that the  tumors in the liver were well encapsulated and dead. In December 2009 the edema and ascites were becoming more problematic. Liver functions were over-loaded due to rapid destruction of the tumor cells resulting in the liver’s inefficient detoxification. ...The patient passed away 2 years after his first diagnosis due to an overload of liver function."

This is quite startling and revealing about the problems related to 3-BP treatment. Even with 11 months of 3-BP treatment the excess of cancer cell destruction was causing severe medical problems. More than any other factor, the inability to carefully control the rate of cancer cell destruction was likely the central contributing factor in the boy's demise. The doctors in his treatment were very well of tumor lysis syndrome at this point and likely had considerable medical expertise to draw upon concerning TLS, though this still largely was insufficient to create a more favourable result.

As the article further notes in the conclusion : "The rate of tumor necrosis due to 3BP treatment seems to exceed all known cytostatic drugs." If this unprecedented power of 3-BP to destroy cancer cells is not tamed, then the potential of 3-BP might be lost.

Questions arise to the strategy used with the patient. The article notes that the cancer had largely disappeared from the patient. The scans show a startling regression of his tumors. Why was it felt necessary to continue to aggressively destroy more tumor mass at the tenth dose? The patient was already overwhelmed by destroyed tumor cells. Giving his body time to clear the cancer cells that had already been destroyed would, in retrospect, have been a much better strategy. *							Report ===							 #54					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 03 February 2015 - 10:02 PM
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mag1, on 03 Feb 2015 - 9:57 PM, said:

Ah, the point you want to make here is that you can deliver a lethal dose to less than 100% of all the cancer cells. If you dose 3BP systemically, you run a risk of either having no effect on any cell, or massively killing many cells at once. A good analogy might be that you want to shoot 30 rats in a room filled with 300 rats. Minicells might let you use 30 bullets to kill 30 rats. Systemic dosing of 3BP might be more like exposing all 300 rats to a toxin like a poison gas. Potentially you end up killing 150+ rats all at once.

So for the patient with a small tumor load, systemic use of 3BP might be okay. For a patient with a terminal condition and high tumor load, minicells might give you a way to limit the collateral damage of tumor lysis by killing off less than 100% of the cancer on each dosing. Edited by pone11, 03 February 2015 - 10:15 PM. *                           Agree x 1 *							Report ===							 #55					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 03 February 2015 - 10:05 PM
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mag1, on 03 Feb 2015 - 10:40 PM, said:

I agree, but it is easy to say and *maybe* it is very hard to do. Someone who is familiar with tumor lysis might be able to add nuance to this. *							Report ===							 #56					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 10:14 PM
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The important point to note is that the article reports that the boy succumbed to liver overload not cancer. There was no reason to push more 3-BP at the tenth dose.

Given the scans from the article it is reasonably clear that the cancer had been well controlled if not cured. Why did they feel it necessary to continue destroying cancer cells? Figure 4D shows a clear control of his cancer while also showing a substantial amount of ascites. *							Report ===							 #57					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 03 February 2015 - 10:29 PM
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mag1, on 03 Feb 2015 - 11:14 PM, said:

The only points I can think of off the top of my head (and it's pure speculation):

* There are not a lot of people with experience in this area, since no one ever "cures" metastatic liver cancer! Literally, the doctors might have been getting their very first clinical experience in this level of tumor lysis.

* They might have been researchers more than clinicians, and maybe they were a little too focused on measuring cancer load and not focused enough on measuring patient well being.

Has anyone looked at using 3BP as a prophylactic? It would be interesting to maybe transfuse it once a year into a healthy person, and monitor the byproducts that are excreted over the next month. For most people it would have no effect because there is no cancer. For those with early stage cancers, it might simultaneously kill the cancer while it is in an early stage, as well as act as a diagnostic tool for the presence of cancer by virtue of the presence of lysis byproducts appearing after the infusion. *							Report ===							 #58					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 03 February 2015 - 10:54 PM
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It raises substantial questions concerning medical competency. This is all the more surprising as there was an ethics oversight committee that presumably was in place to ensure that the best interests of the patient would be the primary consideration and not exploring maximal dosing of 3-BP.

It should be noted that the 3-BP treatment was a substantial success for the patient. Before treatment: "By now, the health condition of the patient had deteriorated, in fact, so far that he could not consume sufficient amounts of food to sustain life... While the patient’s health was deteriorating,...". When 3-BP treatment was started the patient had no obvious treatment options and it might be an exaggeration to suggest that his life expectancy was measured in even weeks. With 3-BP treatment, the patient lived about 11 months with a reasonably high quality of life. The patient "was able to survive a much longer period than expected with an improved quality of life, which is clearly attributable to the treatment with 3BP."

By fully acknowledging that 3-BP treatment in this instance resulted in an overwhelmingly more favorable result, it might encourage others in a similar circumstance to seek such treatment and advance this mode of treatment for those with extremely severe illness. Once it has been widely understood that such cancers benefit from this treatment, earlier interventions might be shown to be even more helpful. It should be noted that large numbers of patients do exist in such extreme end stages of cancer and clinical trials including such patients could lead to rapid clinical results.

Perhaps a 3-BP clinical trial could be conducted in patients with life expectancies of days. Results of such trials might be available in weeks. It is quite possible that such trials could demonstrate statistically significant improvements in survival. Many cancer trials require 5 or more years to generate results which often result in uncertain read outs. For example only with a certain sub-group at a certain stage of cancer or genotype might benefit. Further trials are often required taking yet more years. *							Report ===							 #59					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 04 February 2015 - 08:47 PM
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"About 1 l of ascites fluid was removed and sent to the pathology lab for cellular analysis. An outcome of an increased lymphocyte count with some mesothelial cells, but no malignant cells was obtained. This lack of tumor cells in the ascites suggested that the tumors in the liver were well encapsulated and dead."

A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside J Bioenerg Biomembr (2012) 44:163–170

This is a more complete quote than the one posted above.

This is startling. The article described the patient as having incurable liver cancer as February 2009. In October 2009, the above quote notes that no live tumor cells were found in 1 liter of ascites and apparently the liver tumors might have been destroyed. It would be very interesting to know how much tumor burden was present at that time (from an LDH measurement or a scan). The scans shown in the article show substantial remissions of the tumor masses. *							Report ===						sponsored ad					=== *			Advert Advert:
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===							 #60					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮

Posted 05 February 2015 - 02:05 AM

I met yet another pancreatic cancer patient (early stage, poor guy working a low-end job), so I dug this up for him and whom it may concern. (Pancreatic is perhaps the best test of all generalized anticancer therapies, on account of its hardwall tumors resistant to chemotherapy penetration, and tragically, it's abysmal 5-year survival rate.)

I have more to say but I'm outta time for the moment. This thread is freaking brilliant, so keep it coming, people. I had no idea how ignorant I was about all this. Don't worry about the keywords. Google sees all.

"The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with [pancreatic ductal adenocarcinoma], should be considered." https://www.ncbi.nlm...pubmed/25326230

"We conclude that: i) concurrent use of 2-DG and 3-BrPA has better anticancer effects in pancreatic cancer cells, ii) 3-BrPA impairs the mitochondria of pancreatic cancer cells and induces cell necrosis, and iii) HIF-1α regulates the anticancer effects of 2-DG and 3-BrPA in pancreatic cancer cells." https://www.ncbi.nlm...pubmed/23076497

"The results show that the inhibitors lowered cellular survival and increased cellular necrosis. Mitogenic signaling pathways were affected by 3BP but not by IAA." https://www.ncbi.nlm...pubmed/20392992

^ 2010 -- ignored or WTF?! "Treatment with the anti-glycolytic agent 3-bromopyruvate almost completely blocked cell viability, self-renewal potential, NF-κB binding activity, and stem cell-related signaling and reverted gemcitabine resistance ", i.e. restored tumor vulnerability to the #1 most effective pancreatic cancer drug. Try https://tinyurl.com/oyfm7kt if the link below doesn't work.

http://www.impactjou...iew&path[]=2120 Edited by resveratrol_guy, 05 February 2015 - 02:16 AM. *                               						*							Report *							1						* 2						*							4		* Next Back to Medicine & Diseases · Next Unread Topic →
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Also tagged with one or more of these key
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175 replies to this topic ===							 #61					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 09:57 AM

Keep those compliments rolling in, they feel great!

FDA granted 3-BP Orphan Designation (though not FDA Orphan Approved) in:

Liver and intrahepatic bile duct cancer (03-05-2013) and

Pancreatic cancer (30-04-2014).

[I am not clear about the meaning of the terminology involved. How can the drug have Orphan Designation Status though not be approved?]

FDA granted authorization to immediately begin a phase 1 trial with a commercial formulation of 3-BP on January 11,2013. *							Report ===							 #62					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 05 February 2015 - 12:15 PM

Sorry I'm pressed for time again, but I don't want to risk losing this data dump from Dayspring Cancer Clinic, the 3BP folks. Here's how it goes:

1. A phone consult (onsite preferred) is available for $350.

2. The 3BP IVs are not deliverable alone. They come as part of a comprehensive therapy package for $28,000/month. However, I was told that 3BP is available for "cheap" from various Chinese labs. That might make sense for the nonrich, provided that one could send a sample to a lab for verification via mass spectrometer, HPLC, etc. (Sounds like a group buy...)

3. The State of Arizona licensed their doctor to deliver 3BP in about 12/2014, so obviously they don't have much in the way of statistics yet. Presumably, other doctors throughout the USA will be licensed soon, but I have no further data.

4. Patients are advised to take antiparasitic medication prior to initiating 3BP therapy, because the parasites can eat the 3BP. This makes no sense to me, because the parasites are in the gut if they're anywhere, and the 3BP is intravenous. So yeah, some of their techniques seem goofy, but OTOH if they want to spin around clapping their hands for good luck while delivering 3BP to save lives, that's fine with me.

5. Other aspects of the therapy include: Gerson(ish) therapy, nanosilver, IV vitamin C, chelation therapy (heavy metals removal), and other stuff I'd never heard of. It occurs 9-5, 5 days/week, under doctor supervision.

6. The administrative assistant was very knowledgeable, but unaware of minicells, or 3BP adjuncts such as paracetamol and salinomycin. I have no reason to believe they would oppose these, however.

7. In the interest of clinical analysis, they do a PET scan the first week, then a second one later depending on disease evolution. This could provide high quality scientific evidence of efficacy. Edited by resveratrol_guy, 05 February 2015 - 12:18 PM. *                               						*							Report ===						sponsored ad					=== *			Advert Advert:
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===							 #63					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 12:47 PM

That is another strange part about the German patient report. Why were they simply destroying more of the bulk tumor mass even when his liver appeared to be overloaded? The scans taken after the ninth 3-BP treatment (in comparison to before the start of treatment) Figure 4 on page 5 of http://download.spri...4b6442&ext=.pdfshow a build up of ascites labelled 1 on the figure.

Would it not have made much more sense to simply have treated with salinomycin at this point. Continuing to destroy tumor cells that are mostly not stem cells proved to be very dangerous and ultimately fatal for the patient. After the huge success of 3-BP treatment, targeting the remaining stem cells with salinomycin would have stopped a rebound in tumor growth while the patient's body regenerated his liver and cleared the huge quantity of destroyed cancer cells. *							Report ===							 #64					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 12:52 PM
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Sorry, the above link did not work.

The German report is open access. Go to below url. Don't pay for it!

http://link.springer...0863-012-9425-4

Scroll down to the Volume 44,Issue 1, pp 1-6 hyperlink and click

Scroll down to the article called " A translational study "case report" on the small molecule ...." and click *							Report ===							 #65					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 01:01 PM
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Wonder about the PET scans.

LDH was the primary biomarker used in the patient with metastatic melanoma treated with 3-BP. LDH would likely give you a very good numerical read out on the quantity of metabolically active cancer in a patient. Sure, a PET scan would also be great to give you the precise locations of tumor masses. However, in terms of day to day patient management LDH might be more useful. If a Tumor Lysis problem arose a frequently measured LDH test would pick it up first.

Oh, and LDH tests cost $4.15.

Did you drop the $350 on a phone consult? Wow, taking one for the team. *							Report ===							 #66					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 05 February 2015 - 06:10 PM
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resveratrol_guy, on 05 Feb 2015 - 1:15 PM, said:

Personally, I find it extremely offensive that a cancer clinic wants $28K/month to administer 3BP.

I also feel that these kinds of commercially driven organizations that prey on the hopes of desperate patients are not to be trusted, and specifically I don't trust their ad hoc n=1 reports about "cures". It would raise the credibility of this thread on Longecity if people would call out such results as from a commercial organization and not treat it - in ANY way - as equivalent in value to peer-reviewed scientific research.

It would have value if - over time - people announced other clinics that have a more humanitarian approach to patients that are starting to deliver 3BP therapy. *							Report ===							 #67					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 05 February 2015 - 06:18 PM
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mag1, on 05 Feb 2015 - 1:52 PM, said:

Here is the full text of the study you are referencing in your post as a URL:

http://link.springer...0863-012-9425-4

It was confusing to follow your instructions. In the study you did link - which is not the one you want us to look at - the mention of the German cancer patient is at the end and is very brief.

Here is the study you wanted to link in full text:

http://link.springer...0863-012-9417-4

I see your point in Figure 4, but this thread would benefit from someone introducing correct information about tumor lysis. For example, maybe lysis occurs weeks or months after the cancer is killed, so managing therapy versus lysis levels might actually be an extremely tough thing to do? You think you are killing cancer without lysis, and then the lysis levels creep up on you post-therapy and end up killing the patient before there is time to act.

What is perplexing to me is how can they publish a study like the German Liver Cancer case report in 2012, and here three years later they don't have a published study on someone with an early stage cancer of the same result. To me, THAT is what is criminal, not that they did not account for lysis correctly. How can these people be staring at such dramatic clinical results and not be testing every early stage patient they can get their hands on? Edited by pone11, 05 February 2015 - 06:30 PM. *                               						*							Report ===							 #68					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 09:12 PM
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The profit margin on 3-BP treatment will be extraordinary. Chinese suppliers offer 25 kilogram drums of it with up to 98% purity for a very reasonable price. However, given that many of the people who would be especially interested in the treatment likely have serious illness the prices being quoted for treatment in a regulated medical setting do not seem that outrageous. Many cancer drugs that the FDA approves cost considerably more money than 3-BP treatment would and often these approved treatments have surprisingly small effectiveness.

3-BP treatment has yet to fully conquer the aura of invincibility that cancer has acquired throughout human history. Many would find it a reasonable trade-off to pay the quoted fee in return for being treated in a setting where high standards of professional conduct would be strictly enforced by the American legal system.

Of course, the great irony is that the only patient reports that we have been endlessly discussing here are from non-American non-commercial groups who have published n=1 studies in peer reviewed scientific journals which quite possibly have been positively selected based on response. It is a very large concern that there are people who have been treated with 3-BP who have not benefitted from 3-BP and, thus, their clinical reports were not deemed worthy of publication. If clinics could simply give us sequential patient reports of those treated with 3-BP, it would give us a better idea of the effectiveness of 3-BP.

Americans let their freedoms be taken away from them by the centralization of the medical regulatory system. How surprising, central planning failed terminally ill cancer patients! Wouldn't of guessed that could happen in a million years. What could possibly go wrong in having one centralized decision making process to authorize innovative medical choices? The 3-BP researchers had obviously given up on America ever being a clinical leader with 3-BP (probably after considerable efforts trying to convince politicians and regulators). It took ten years for 3-BP to make it to the clinic (though in a different country). Right to Try Laws will finally stop the unconstitutional denial of patient's rights.

After developing a potentially massive breakthrough product (3-BP), we now must extend heartfelt gratitude to Germany for having a regulatory system that allowed a hospital ethics board to authorize 3-BP treatment to a boy with end-stage terminal metastatic illness. It is all the more surprising as the only published research to that point was in animals. Choosing to treat with such minimal information took courage and moral wisdom. German law allows doctors to exercise their best professional judgment in the treatment of their patients. It is deeply regrettable that America allowed the fate of terminally ill patients to be decided by a highly politicized democratic process. In the published patient report from Germany, the patient did benefit from their regulatory environment. If 3-BP results in a Nobel prize, then the Germans should earn some recognition for their contribution. For several years, the German report was the only published example of a human treated with 3-BP. Some acknowledgement of the failure of centrally planned medical regulation seems appropriate.

Sorry for the confusion with the url. I tried to grab the url for the article though the publisher seemed to be blocking it. The article is open access, though on the publisher site they want people to make a payment to read the article. They made it a little confusing, though if you follow the links I suggested then you will eventually get to the free article. *							Report ===							 #69					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 05 February 2015 - 09:29 PM

Catching up...

"Ketogenic diet should be an additive therapy here, as would be any other pro-oxidative therapy."

By "pro-oxidative", I assume you mean "pro-OXPHOS" because a ketogenic diet would result in reduced ROS per unit of energy released. Ozone and hyperbaric oxygen do do seem like useful anticancer therapies, but I would not engage in them prophylactically, as the cell membrane damage can't be a good thing in the long term.

"The below url provides a good introduction to minicells. On page 5 of the article, (Figure 1A) notice that 520 nanograms of monastrol 4 times per week loaded onto minicells cured the mice of cancer! NANOGRAMS!"

I find this hard to believe, but certainly it deserves an attempt at reproduction of results. Just the same, I do  think minicells are a reasonable adjunct to 3BP. In cancer treatment, if you want to follow the "kill 'em all" approach (which I have certain statistical doubts about), then the only way to win is in fact to kill every malignant cell. Killing 99.999% of them with 3BP is awesome, but insufficient. If minicell usage tips the balance to 100%, then we win. So I think patients should at least be given an informed choice when there is an appropriate way to exploit a minicell strategy. Or, for that matter, a set of heteromorphic minicells all delivered simultaneously, aimed at different vulnerabilities.

"Possibly the molecule needs to be as simple as 3-BP to work and perhaps this means that there is a problem making the drug different enough from 3-BP to file a valid patent."

BINGO! ...and we wonder why there has been so little research

"There is no compelling argument to be made that experiments must rigidly continue with an hypothesis that has been shown to be invalid."

Well said. This is the essence of the dirty data revolution, which is for better or worse turning ye olde scientific method from a process of discrete steps into a smeared out continuum of evolving understanding linked to constantly adaptive experimentation. This isn't a new idea; it's a precursor to the Kurzweil singularity, at which point experiment and technological evolution are so tightly linked in time that only the machines understand the significance of either.

"3-BP is a strong candidate for preventative cancer management."

I wouldn't use it as a prophylactic. We can't afford to have cancer somehow learn how to avoid it. I'd prefer proOXPHOS (e.g. c60oo) as opposed to an antiglycolytic.

"full text for the rat brain cancer study"

Nice one, thanks!

"Tumor Lysis Syndrome is a completely preventable and treatable medical condition."

Agreed. For one thing, conventional hemodialysis could probably avert this entirely. For large tumors, it could be started preemptively once 3BP has had a chance to exit the blood stream and settle into tumor cells. Not to mention, let's try to use 3BP way before we're dealing with stage 4 (e.g. visit a banana republic in stage 1).

"[3BP might] act as a diagnostic tool for the presence of cancer by virtue of the presence of lysis byproducts appearing after the infusion"

Pure genius! It would be beyond a cancer scanner; it's a how-close-are-you-to-cancer scanner. And yet, so comparatively low-tech.

"Oh, and LDH tests cost $4.15."

I agree with cheap and accurate, if we're talking about assessing disease progress with respect to a specific type of tumor. I was just saying that PET is a good catch-all way to survey disease status with respect to glycopathology, in order to "prove" 3BP across many different cancers.

"Did you drop the $350 on a phone consult?"

No. But the administrative assistant was quite helpful and forthcoming.

"Personally, I find it extremely offensive that a cancer clinic wants $28K/month to administer 3BP."

Well, it certainly isn't practical for most of us. OTOH I do  think they can provide good data, even if indirectly so. It's amazing what certain software architectures are able to do by way of separating hype from fact, using methods not unlike the Bayesian methods developed for spam filtering, especially if we could review the results of many different clinics. (For instance, IBM Watson seems to employ tools like this.) And it's not like they have zero social liability for publishing any random BS.

Bottom line, I cannot emphasize this enough:

1. Cancer is a computer, all of whose processors must be shut down before any one of them learns to circumvent all of the applied therapies.

2. The probability of any given cancer cell (or cancer stem cell) surviving the attack decays exponentially with the (linear) number of applied therapies, assuming that they are orthogonal (target independent vulnerabilities). The precise decay exponent varies with the particular therapy. Another way to think of this is that the size of the surviving population is  the product of individual survival factors, each of which associated with one of the orthogonal therapies.

3. Whereas nonmetastatic tumors (which we sort of don't care about in this context) grow at a rate approximating (radius^2 per unit time) -- a single ball growing one surface layer at a time, essentially; metastatic ones grow exponentially because the circulatory system affords them effectively unlimited surface area (radius^(N-1)/time in an N-dimensional space, if you like). Thus we have a positive exponent which must be overcome by the negative exponent in #2 on a sufficiently protracted basis in order to reduce the viable malignant cell population to nil before the patient dies.

4. It is often easy to accomplish an NED (no evidence of disease) state, but this is far from a cure due to cancer stem cells, and even just tiny numbers of "normal" cancer cells that survived the attack. So what we need is an absolutely overwhelming assault from day one, then very sensitive blood tests (e.g. Miroculus or the lysis scanner just invented above) to verify total annihilation. But this is hard to prove. So we have to hope that the resurgent cancer, were it to return, would remain susceptible to 3BP. It might well be, because glycolysis is so fundamental to aggressive cancer, but this is the gamble. The alternative, apart from applying conventional therapies or doing nothing, is glycolytic welfare (as opposed to warfare): Logically, there should be a therapeutic benefit to providing the products of glycolysis, via minicell, in a "tumor welfare" system, which equilibrium principles would suggest should thwart actual glycolysis, just as people on barely-sufficient welfare tend to avoid work. But I'm lacking for published studies here, and maybe this strategy is best reserved for recalcitrant end-stage tumors. Edited by resveratrol_guy, 05 February 2015 - 09:37 PM. *                           Good Point x 1 *							Report ===							 #70					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 09:45 PM
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Tumor Lysis Syndrome is a preventable and treatable problem resulting from the sudden destruction of a massive amount of tumor. In the German report, the patient went into a coma after the second treatment with 3-BP, due to Tumor Lysis Syndrome, and was not expected to live. Yet, the patient made a spontaneous recovery.

The episode that proved fatal was a result of the liver not being able to handle all of the destroyed tumor cells. The article described this as liver overload. It is not entirely clear if this is exactly the same thing as Tumor Lysis Syndrome. Tumor Lysis Syndrome is preventable and treatable. It is possible that the liver failure was not a treatable problem. However, the liver failure was a result of the same process: an unmanageable amount of destroyed tumor cells. The patient seemed to be contented in the picture in the article at the time of his birthday. It is regrettable that the focus continued with the tumor and not recovery of the liver. Salinomycin would have blocked and cancer regrowth. This would have avoided destroying the tumor bulk composed of non cancer stem cells that have not shown to be essential for tumor development.

A more successful treatment outcome might have resulted if destroying more tumor cells had not been pursued so relentlessly. After a year of intensive 3-BP treatment it is not hard to imagine that the patient's liver was under extreme stress. The article notes, however, that the liver was in fact continuing to regenerate even near the end. 3-BP resulted in a positive result for the patient, one which likely would have been even more successful if a cancer regrowth blocking strategy (for example, with salinomycin) had been adopted once the stress on the liver had been noticed (for example in figure 4 after the 9th treatment). *							Report ===							 #71					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 05 February 2015 - 10:20 PM
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pone11, on 05 Feb 2015 - 7:18 PM, said:

From the case report paper, it sounds like lysis happens pretty rapidly, and falls off pretty rapidly as well. It looked like it more or less spiked after each dose of 3BP. Yet, it remained a problem throughout treatment, while if things were working as you'd think, the tumor load would have kept falling and TLS would cease to be a problem. Maybe what was happening was that there was a lot of dead tumor tissue that was continuing to degrade. It sounds like his liver was too damaged to recover, or to recover in time.

Speaking of criminal, why did it take the ethics committee a month to ok 3BP treatment? Maybe if he'd had it earlier, instead of toxic crap like cisplatin...

I too am appalled at the $28K/mo number. I hope extensive lab work and imaging can at least partially justify that, but I kinda doubt it. I also find it distasteful that they repeatedly mentioned their "patented and proprietary" formulation of 3BP, turning a badly written case report into an advertisement. I recall once hearing someone claim that if it wasn't for everyone trying to get rich, we would have cured cancer a long time ago. Might be something to that... *							Report ===							 #72					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 10:26 PM
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I am pushing hard to get a new topic tag added to this thread: "The Cure for Cancer?"

Too many of the cancer threads on this forum are on topics that do not offer hope to end stage patients. Eating your vegetables will not cure severe end stage cancer.( A point largely accepted by the alternative medicine community.)

I want the topic tag "The cure for Cancer?" to offer examples of cancer patients who have had overwhelmingly severe illness and responded to an innovative treatment as published in a scientific journal (perhaps this topic tag could be moderated to ensure it complies to this intent). 3-BP is one treatment which would have earned this distinction, there are also a few others (e.g. CAR T cells).

So we're throwing down the gauntlet. Any published cancer result that qualifies can get in the ring!

(If someone knows how to contact a moderator to change the topic tag, then it would be very much appreciated if this were done.) *							Report ===							 #73					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 05 February 2015 - 10:27 PM
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mag1, on 05 Feb 2015 - 10:12 PM, said:

Most insurance companies won't cover the costs of an unregulated and unproven therapy. So quite likely a lot of that $28K is out of pocket. The substances being used by Dayspring are not expensive. That $28K is almost pure profit to the cancer clinic for services rendered.

There is a world of difference between cancer researchers who do an n=1 trial and publish the results in a peer reviewed journal and "Dayspring Cancer Clinic". It's frustrating to me that some of your posts make the two cases sound equivalent in quality. A commercial entity with no research ties can hide bad data, distort good data, and simply present bad data in an incorrect way in order to market their for-profit service. You will lower the quality of this thread by using those kinds of organizations as data points for reporting results.

I agree with you the FDA has destroyed freedom significantly. They have also destroyed our economy, making it possible for drug companies to charge any price they like for therapies that get through the regulatory process. *							Report ===							 #74					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 05 February 2015 - 10:36 PM
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resveratrol_guy, on 05 Feb 2015 - 10:29 PM, said:

Low tech, low cost, fairly low risk, and actually therapeutic if you have very early stage cancer.

It would also widen the experience of oncologists with 3BP, and that directly feeds into willingness to use it for later stage cancers. Edited by pone11, 05 February 2015 - 10:55 PM. *                               						*							Report ===							 #75					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 05 February 2015 - 10:45 PM
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niner, on 05 Feb 2015 - 11:20 PM, said:

I want to put nuance on this. The reason that some cancer therapies cost $30K/month (or more) is that we have a dysfunctional medical delivery system:

1) We socialize the delivery of health care through Medicare, but we do nothing to control cost.  You cannot socialize delivery without price controls otherwise you are enabling monopolistic pricing, which is what  we have in the US today.  I'm not advocating any specific type of system.  I'm simply saying you cannot write blank checks without suppliers abusing you and jacking up prices.  This is a point about economics and not a point about social preference or politics.

2) The FDA prevents competitive products from getting into the marketplace, which limits price competition and further empowers monopoly pricing.

The "drugs" being used by "Dayspring" are not expensive. They are mostly commodities like Vitamin C. 3BP is also cheap. They are simply taking the price of $28K based on what proprietary drugs cost, and passing all of that back to themselves as pure profit for services. I find that obscene and abusive, and it tells me they care about money more than saving human lives. *							Report ===							 #76					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 05 February 2015 - 10:53 PM
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mag1, on 05 Feb 2015 - 11:26 PM, said:

People don't search based on complicated tags. "The Cure for Cancer" in a tag won't increase traffic. Cancer is the right tag.

I don't think we want people throwing non-3BP related topics into this thread. Why would you do that? You will have every quack cure that isn't even scientific get thrown in by some person acting on a hidden commercial interest. You have a powerful and specific solution in 3BP. Don't hide it. The complexity of this conversation shows that 3BP alone is a complicated topic and there will be a lot of new research and subtopics to explore in the next few years.

To the admins:  is there any feature on the site that would let us cross link this topic into other forums? I think it could be topical to several discussions, and I think the thread is important and deserves visibility across the site to a wider audience.

What I might recommend:   go sign up on other cancer blogs, and point them to this thread. But I would caution you before doing that not to do it in unscientific forums. The beauty of Longecity is that it seems to attract engineers, scientists, and lay people with a respect for science. I for one am extremely tired of participating in other forums that are health related. Most people can't read or understand science and the discussions become emotional and factually not very valuable. *							Report ===							 #77					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 11:08 PM
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I would cut the commercial cancer clinics some slack. There is still considerable uncertainty about how to safely provide 3-BP treatment.

The 2 published reports on cancer patients who received 3-BP noted extreme anti-cancer responses, though both patients ultimately

succumbed, not to cancer, but to what might most accurately be described as iatrogenic causes. Knowing how to manage potentially

fatal complications (such as Tumor Lysis Syndrome) and establishing the correct dosing schedule of 3-BP are complex issues that are best

managed by highly qualified doctors.

In fairness, the criticism of the treatment received by the patient in the German report might be entirely misplaced. It is quite possible

that no treatment regimen would have resulted in a better outcome than that was achieved. (This is difficult to fully assess).

However, these are exactly the sort of criticisms that doctors are routinely exposed to and might be expected to receive until 3-BP

therapy has been fully tested in a range of clinical populations.

If I were to now be suffering from a similar extreme end-stage cancer, I would be very grateful if a cancer clinic took $20,000 from me, treated me in

their official medical clinic, and pulled me back from the other side. I could always try and save a few bucks and round up some kids who passed high

school chemistry. They could mix up some 3-BP in my kitchen. That would be nuts! People go to medical school and they earn degrees in medicine.

They become doctors. It is too early to be grumbling about the cost of curing cancer. When all the problems noted on this thread are worked through,

then we might reach the point where curing metastatic cancer will have to be postponed so that a patient can watch their favorite TV show or haggle

over the cost. We have not reached such a point yet. *							Report ===							 #78					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 05 February 2015 - 11:27 PM
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I was thinking that we could develop awareness of powerful cancer treatments through the topic tag. The problem with the tag cancer is that it is so all encompassing that people throw it into the list even when the thread does not have a clear relationship to cancer. For example, one of the most highly viewed threads with the topic tag cancer is actually about a cancer drug that might treat Alzheimer's. Many of the other highly viewed cancer threads also are not specifically focused on the treatment of severe cancer.

If we could grow traffic to topic tag "The Cure for Cancer?" it would highlight the success of 3-BP. Nothing would have to change on this thread.

The topic tag might encourage others to add the same topic tag to their thread and include other cancer treatments that have demonstrated similarly amazing results as 3-BP. There are a few other stunning cancer cures that are currently emerging. For example, CAR T cells have also cured patients with no other treatments choices of severe metastatic illness.

This thread seems to be the most relevant of all the cancer threads in offering cancer patients with severe illness a possible treatment. The forum does not make it easy for people to find threads such as this. This thread is still flying below the radar. It would be great if the forum had more tools to locate successful threads such as this. For example, a method showing a graph of activity (views) in threads and allowing ranking of threads by such changes in views. Currently, the ranking system favors threads that have existed for many years, even when they do not offer innovative solutions. *							Report ===							 #79					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 02:20 AM
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mag1, on 06 Feb 2015 - 12:08 AM, said:

I recently had a kidney doctor tell me that he gets paid by the insurance company only $200 to come into a hospital environment and provide a consultation on a kidney failure patient. He is providing life-and-death advice to someone who is incredibly ill, and regardless of the time he puts in he makes $200. He then made the point to me that the same service provided by a large hospital is being billed to insurance for $2000. There are exceptions for some specialties, but largely bread and butter physicians are not the ones getting rich in the current environment.

So your first mistake is that you believe it is the doctors who are getting paid well when you give that $28K to the cancer clinic. Probably they aren't. It's mostly pure profit for the cancer clinic.

The two parties that are growing vastly wealthy, at the expense of US taxpayers are:

1) Pharmaceutical companies, that can charge monopoly prices while the government hands them blank checks.

2) Large hospitals, who have learned to game the system with medicare, and who have enormous negotiating power against insurance companies.  This is why the insurance companies are able to bully small physician practices, but bend over and overpay large hospitals.  A large metro-area hospital now pays $1M per year salaries to its key executives.  That says everything about how much profit those hospitals make.

In a competitive environment no one makes $28K/month per patient providing some IV infusions and then some monitoring and blood work post transfusion. In a competitive environment, a commodity like 3BP should be infused at around $175/visit, and even that is pretty expensive. The overcharges by the parties in 1) and 2) have so distorted every person's thinking about health care costs, that somehow a clinic is able to give you vitamin C transfusions and some 3BP and no one blinks at paying $28K/month for it. As a taxpayer paying for the abuses, and as a human who might someday need to pay out of pocket for these services, I find it all pretty disgusting. Edited by pone11, 06 February 2015 - 02:38 AM. *                               						*							Report ===							 #80					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 06 February 2015 - 05:10 PM
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I added the tag "cancer cure" to this thread. It's better for tags to be short and simple; it's not likely that someone would think to search for a longer phrase, particularly with a question mark. If there are other threads that should have such a tag, I'll add it if someone points me to the thread.

Question:  How is it that 3BP only takes out cancer cells? If it's an alkylating agent, those are typically very indiscriminate. *							Report ===							 #81					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 06:19 PM
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niner, on 06 Feb 2015 - 6:10 PM, said:

3BP exploits the overexpression of the HK2 enzyme in nearly all cancers. Glucose travels into the cancer cell because it has so many gateways on the cell surface, apparently activated by HK2. 3BP looks like a nutrient and somehow slides in through these gateways.

The beauty of this is that most "normal" cells don't have enough of these gateways to let in substantial amounts of 3BP into their cytoplasm. You are right if the 3BP somehow got into normal cells it might kill them too. But the mechanism exploited preferentially overdoses just the cancer cells with these HK2 activated gateways for glucose.

That's why it would be very hard for cancer to "evolve" past this drug. Cancer would need to change its entire metabolic strategy. At that point you wonder would it even be the same disease, and would it progress as rapidly?

See reference:

http://link.springer...0863-012-9425-4 *							Report ===							 #82					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 06:29 PM
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It is important to remember that dosage matters tremendously with 3-BP.

In one experiment it was found that all animals died within minutes after being administered a larger dose of 3-BP than that needed to destroy their cancer. 3-BP shuts down cellular in normal cells when given at elevated doses.

3-BP is a very dangerous drug at the wrong dosages. As has been mentioned on this thread even for people with large tumor burdens administered a small therapeutic dose, 3-BP can be a very dangerous drug. *							Report ===							 #83					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 07:23 PM
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mag1, on 06 Feb 2015 - 7:29 PM, said:

Fantastic points. Maybe you could post URLs to FULL TEXT for the 3BP overdose study?

By the way, learn to use Sci-Hub. It's a Russian site that usually finds full text if you search on the full title of the study. I would say it bats about 90%!

http://sci-hub.org/ *							Report ===							 #84					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 07:29 PM
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mag1, on 06 Feb 2015 - 12:27 AM, said:

People don't browse tags. So how will anyone find a tag named "Cure for Cancer"?

I supposed you could ask for a new topic on Cancer, but doesn't that lower your views instead of increasing them? You are already the #1 thread in the Medicine & Diseases forum. Your thread is marked "Hot". I don't think you can get better than this? If there were a Cancer forum, then people in Medicine would miss this important thread.

Keep in mind that Longecity is not a huge place. It's mostly the hardcore scientific types. I think that is a great level at which to have the discussion too. But you won't get 500 people here.

Again, why not contact the admin and ask if there is a way to cross link the thread to other forums? Maybe they will allow you to post invitations to this thread in other relevant (!) forums and then occasionally bump those invitations to keep them current. *							Report ===							 #85					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 06 February 2015 - 08:38 PM
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pone11, on 06 Feb 2015 - 8:29 PM, said:

People might browse tags if they were consistent, sensible, and finite in number. The problem is that we let people create any random tag that they want, so tags are all over the map. I think it would work a lot better if we had a consistent set of tags to choose from. This would require someone to come up with a list, and we lack manpower. We'd still need to let people add their own tags because the list probably wouldn't be all-inclusive.

There are a lot of guest logins, although many of them are search engine web crawlers. We get a lot of traffic though.

Most people here read the forums using the "Recent Topics" button, which is the first item on the Search menu. This shows all recent threads from whichever forums you are subscribed to, which defaults to all of them. The use of Recent Topics with a well-tuned subscription list is the only way to go, IMHO. *							Report ===							 #86					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 08:39 PM
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This is from one of the 3-Bromopyruvate patents. Priority Date Dec18, 2006 http://www.google.co...2114413A1?cl=en

From Example 24 of the patent:

In rats,

"In order to determine the therapeutic dose of 3-bromopyruvate for intravenous (FV) administration, a dose-escalation study was conducted in normal Lewis rats (non-tumor bearing). Each group of animals (6 rats per group) received incremental doses of 3- bromopyruvate intravenously (2.5mL of 5, 10, 15, 20, 25 and 5OmM 3-bromopyruvate). The animals were observed for a period of 3 weeks and watched for any evidence of toxicity. The therapeutic dose was found to be 2OmM. At the highest dose  of 5OmM, all the animals in the group died within 15 minutes. It was observed that all of the organs were found to be normal by histopathologic analysis and that there was no evidence of corrosive effects of 3-bromopyruvate even at that high dose. All doses lower than 20 mM were well- tolerated and caused no deaths."

In rabbits,

"...Although these doses (2.5 and 5 mM) were 0.5 and 1 log higher than the 0.5mM dose previously investigated, these doses were well within the IV therapeutic dose established in rats and rabbits. It was observed that the 5mM concentration of 3-bromopyruvate completely destroyed the tumor,  but also caused widespread necrosis of the surrounding healthy liver resulting in the death of all the rabbits within the group. However, all  of the other major organs were found to be completely uneffected on histopathological analysis at necropsy, indicating a predominantly loco-regional toxicity of 3-bromopyruvate when delivered intraarterially. The lower dose of 2.5mM also achieved complete tumor destruction, but the surrounding healthy liver still showed large areas of necrosis and fatty changes making the animals extremely sick and barely able to survive for more than 48 hours after treatment."

Possible implications in humans,

"...Since patients with HCC also suffer from underlying liver disease such as cirrhosis and hepatitis, an important translational consideration for therapy is the absolute necessity to protect and preserve healthy liver parenchyma. To lessen the degree of liver toxicity, different temporal modalities of intraarterial injection were tested. One possibility was that such a large volume, delivered within the short time of 2 minutes may have added physical and chemical toxic effects on the liver. Thus, a  1-hour continuous infusion and a serial infusion of 2 boluses administered an hour apart were compared against the original single bolus dose."

It is not clear whether these comments might have bearing on the German patient. Was an autopsy performed? Did they investigate possible liver toxicity of 3-BP? Perhaps the assessment of liver overload as being being responsible for the demise of the patient precludes the possibility of direct liver toxicity caused by 3-BP. *							Report ===							 #87					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 08:43 PM
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It is too bad that we can't do dual searches.

For example, the most viewed AND within the last year AND topic tag cancer.

This thread is hot (I want red hot), though so many of the cancer threads from years ago clog things up. This thread is listed on the second page for cancer topic tags by views, while none of the threads listed earlier have had any substantial recent activity (some in years). *							Report ===							 #88					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 09:01 PM
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mag1, on 06 Feb 2015 - 9:39 PM, said:

This sounds like exactly what happened to the German liver cancer patient. That in turn suggests it was not lysis that got him. It was direct action by 3BP to destroy normal liver cells that were adjacent to the cancerous cells.

The text above makes it sound like "normal" cells that are adjacent to a cancer cell become predisposed to uptake larger amounts of 3BP that prove fatal. Perhaps cancer takes over normal cells in phases, and one of the first phases might be to upregulate HK2 and allow the cell to take in more glucose. If that happens before other evidence of cancer affects the cell, it might be seen as "normal" to the outside. But metabolically it is subject to the killing action of 3BP because it is able to pass in too much 3BP to the cell. 3BP doesn't target cancer. 3BP targets cell receptors that can uptake glucose and 3BP. If normal cells are already modified with many such receptors, they too are subject to the killing action of 3BP.

That's very problematic. I don't know how they overcome that. And if this effect is present how did the German liver cancer patient survive so many 3BP therapies? Edited by pone11, 06 February 2015 - 09:03 PM. *                               						*							Report ===							 #89					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 06 February 2015 - 09:11 PM
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pone11, on 06 Feb 2015 - 7:19 PM, said:

It's also reported to hit GAPDH. I'm just surprised that it doesn't hit everything under the sun and therefore have a lot of off-target effects and toxicities. I suppose that it actually does, at a high enough dose, and we just got lucky due to a quirk of it looking like a nutrient and getting delivered via monocarboxylate transporters. *							Report ===						sponsored ad					=== *			Advert Advert:
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===							 #90					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 09:17 PM My whole idea with the topic tag (now designated) "cancer cure" is to build up a brand following for massively successful cancer drugs.

3-BP qualifies. What other cancer drugs have induced Tumor Lysis Syndrome or effectively treated someone with end stage liver cancer?

The current topic of cancer is not showing any of these recent results. The topic tag "cancer cure" could help focus attention on the stunning recent results in cancer research. Oncologists have been startled over the last few years at the emergence of effective cancer treatments in late stage patients. These results should be reported onto this forum in an easily accessible way. Perhaps this sense of information organization could spread throughout the forum.

The topic tag cancer has become too unfocussed. People who are searching for quick access to a specific dimension of the word cancer should not have to read through the dozens of threads (many of which have nothing to do with addressing possible treatment options for end stage terminal cancer) to find a specific sense of the word cancer.

If you were to go to a reference library you would not find books and articles on cancer randomly thrown on the floor. Organization is vitally important when you have a large database of information. This forum could do much better at organizing the information contained in it.

A simple approach is already available. Use the topic tags in a consistent way to provide order. That is what I want to do with the topic tag cancer. I will start a thread explaining the idea and others might start threads in the spirit of what I have in mind for the topic tag cancer cure.

By the way does anyone know the answer to the million dollar question: What is the industrial use of 3-Bromopyruvate?

When you go online, there are Chinese wholesalers that will accept orders for 3-BP at a minimum order size of 25 kg. Some of these suppliers note that they could supply 1000 tons per month of it. What possible industrial use is there for so much 3-BP? Curing the patient in Germany took 128mg doses! The huge industrial application of 3-BP (more than anything else) clarifies the difficulty anticipated in patenting it.

The answer is not easily found online (if it is even present).

[Hint: The answer, if correct makes total sense.]

Anyone?

(Accept rain checks?)

Page 4

175 replies to this topic ===							 #91					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 09:30 PM

mag1, on 06 Feb 2015 - 10:17 PM, said:

3BP may be a pseudo-pyruvic acid substitute, or would be used in similar situations.

Pyruvic acid is a starting material for pharmaceuticals like L-tryptophan, L-tyrosine and alanine, as well as L-DOPA. It is used industrially in crop protection products, polymers, cosmetics, and food additives.

This article is about generic pyruvic acid applications:

http://link.springer...7/s002530100804

I absolutely love that 3BP is being mass produced for many applications, and the Chinese are heavily involved in that. Nothing the FDA can say or do will stop its production at this point. Thank God for miracles.

Edited by pone11, 06 February 2015 - 09:39 PM. *                               						*							Report ===							 #92					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 09:39 PM
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Not bad. That is pretty close.

$1250 per ton to make pyruvate. It would be interesting to know the production process used to make 3-Bromopyruvate. The impurities would then be known.

From what I understand, it is used as a fungicide which completely makes sense. Shutting off cellular respiration would do it. *							Report ===						sponsored ad					=== *			Advert Advert:
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===							 #93					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 09:51 PM

Therein lies the problem: without a patentable product 3-BP could just sit there.

No one might bother developing it. Without some profit motive it could go nowhere. The company developing it has decided to wait over 2 years after the FDA gave immediate clearance to start a phase 1 trial. That could cost a lot of money as the patent clock is ticking. The company recently stated that the trial might be further delayed until this spring.

There would be too many lingering questions about safety and effectiveness without proper clinical trials for it to become a widely accepted treatment. There is so much uncertainty now surrounding 3-BP as a treatment. 3-BP needs some sort of profit driver to move forward. Knowing that Chinese suppliers could supply thousands of tons of high grade product at minimal cost would be a problem.

And of course 3-BP could displace the many high priced cancer pharmaceuticals, many of which have never shown impressive effectiveness. *							Report ===							 #94					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 10:09 PM
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The quote from the patent was noting toxicity at certain dosing ranges. It is important to read the patent further to understand the context when used in the dose range of the German patient. The patent was filed from the Johns Hopkins group. The Johns Hopkins group was also involved in the care of the German patient, so the information on toxicity from the patent would have been known to them.

It should be noted that the German patient article stated:

"Regeneration of liver tissue was also observed and the data are being analyzed for future publication."

and,

"Despite regeneration of the healthy liver cells, this process apparently could not compensate adequately for the rapid destruction of tumor cells and could not detoxify the dead cancer cell debris fast

enough."

and,

"A patented and proprietary formulation of 3BP is safe at the concentrations (2–3.5 mg/kg body weight) employed for TACE delivery in humans. No major cyto-toxicities of this specially formulated 3BP have been observed. Please note that unformulated 3BP may be harmful in some cases."

and,

"Liver regeneration is not inhibited by 3BP treatment."

The article is claiming 3-BP was not directly toxic to the liver.

An autopsy would have provided confirming evidence. Edited by mag1, 06 February 2015 - 10:10 PM. * Quote *							Report ===							 #95					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 10:15 PM
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mag1, on 06 Feb 2015 - 10:51 PM, said:

If it is really a cure, the cat is out of the bag and it cannot be stopped. The way drug companies kill something like this is getting the FDA to shut down production. They can't do it, and FDA cannot touch people outside the US from experimenting, treating, and publishing research.

I suspect this is how 3BP will work out in the US:   Cancer doctors will be trained by their masters in the drug industry to use 3BP as an adjunct to their toxic drugs. The pharmaceuticals will claim it is their poison that kills the cancer even though it was 95% just 3BP. They will all struggle to manufacturer "studies" that show that 3BP + <insert-poison-here> is 5% more effective than 3BP alone, and then use that fact to justify charging $100K more for the therapy. Groups will also develop "proprietary" versions of 3BP, which is fine if they add value.

There is a chance that one or more groups - in or out of the US - will develop therapies using 3BP alone that are effective for early stage cancers and charge for that therapy at extremely low prices. Given the climate of greed, corruption, government mismanagement of costs, etc, I doubt it will happen. But it could happen and I will say a prayer for it. Edited by pone11, 06 February 2015 - 10:31 PM. *                               						*							Report ===							 #96					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 10:29 PM
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mag1, on 06 Feb 2015 - 11:09 PM, said:

The fact that liver regenerates after 3BP treatment says nothing about whether "normal" liver cells might have been destroyed during 3BP treatment. They are playing with words. mag1, on 06 Feb 2015 - 11:09 PM, said:"" They make a claim that "apparently" the process could not compensate for destruction of the tumor cells. Where is the proof of this claim?

I am skeptical because page 169 of the German liver report says they are "surprised" by the ascites that started showing up in late 2009:

http://link.springer...0863-012-9417-4

Since they didn't understand that result, or autopsy after death, this leaves open the possibility that the 3BP treatments did in fact destroy some healthy liver cells unexpectedly, just as they did in the animal studies you linked in rabbits and rodents. And I trust those animal studies, which provided very thorough and compelling autopsies of the animals more than I do a hearsay n=1 human study where there was no  autopsy.

Why are there no human studies on early stage cancers of different types? It's unbelievable that these have not been published. Edited by pone11, 06 February 2015 - 10:34 PM. *                               						*							Report ===							 #97					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 06 February 2015 - 10:46 PM
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Yeah, I think the toxicity of 3BP is non-trivial. Things like this are usually more toxic and less effective than they first appear, once they get into serious well-run trials with a lot of patients. As to the financial aspects of this, the Chinese product that's made in ton quantity is not a pharmaceutical grade. It's probably closer to what chemists call a "technical" grade, or maybe worse. If you want to go into humans, you need to develop a manufacturing method that is extremely clean. You can get a patent on the manufacturing method, if not the molecular structure. You can develop a proprietary formulation, and patent that. If you trial and get approved a specific formulation, that's what the patients will get, and their insurance carriers will pay through the nose. There are plenty of prescription drugs that are just fancy formulations of well known old compounds. That's not a scam-- the formulation will make or break a drug. It's the difference between a patient that walks out of the hospital versus leaving in a bag. *							Report ===							 #98					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 10:50 PM
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The section quoted from the patent was looking for maximal doses. They were actively seeking out doses that would be toxic. These doses were much higher than those intended for therapeutic use. At the intended therapeutic dose, 3-BP was found to be non-toxic to the animals.

Example 24: Determination of optimal dose, tumor response, toxicity and delay of tumor progression.

"All doses lower than 20 mM were well- tolerated and caused no deaths. In addition, there was no evidence of clinical distress (lack of appetite, urination, or significant change in body weight). Analysis of  major organs (brain, lung, heart, liver, kidney, spleen, stomach, G.I, bladder and skeletal muscle) at necropsy confirmed the safety of these doses, as all were without any damage. These results therefore established the therapeutic dose of 3-bromopyruvate to be 2OmM or 16.8 mg/kg. In addition, an acute toxicity study was performed to determine the effects of 3- bromopyruvate administered FV. Based on the data acquired in rats, rabbits (2 animals per group followed for 1 week) were  given 25 ml of 15, 20, and 25 mM 3-bromopyruvate as a single IV dose (i.e., using dose identified for rats). Results of the rabbit experiment  paralleled those of the rats with 2OmM or 16.8 mg/kg 3-bromopyruvate calculated to be the therapeutic dose, with no evidence of any organ toxicity."

Figure 4 shows liver health improving after the 9th treatment.

It should be noted that the dose reported as safe (not clear what exact dose was used on the patient reported as 125 mg etc.) in the German report was 2-3.5 mg/kg.

The 3-BP treatment appeared from simple observation to be non-toxic and well tolerated. After the first round of dosing, the patient had no side-effects. The picture taken on his birthday shows what appears to be a happy and healthy person. No mention of pain medication is noted in the article. *							Report ===							 #99					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 10:52 PM
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niner, on 06 Feb 2015 - 11:46 PM, said:

Fine, but let's say that Chinese 3BP is technical grade and costs $125/ton. Along comes Group X that develops a proprietary process to make pharmaceutical grade 3BP at $1M / ton.

Any competitor worth his salt goes to the Chinese and asks for a pharmaceutical grade at $500/ton, and I have no doubt they will get it.

Competition is a beautiful thing, when the free market is allowed to work. *							Report ===							 #100					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 10:58 PM
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The cell toxicity studies with 3-BP showed no toxicity to normal cells over the range of therapeutic dosing used to destroy cancer cells. *							Report ===							 #101					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 06 February 2015 - 11:03 PM
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pone11, on 06 Feb 2015 - 11:52 PM, said:

Competition and the free market are great, but they can't get blood from a turnip. The requirements for active pharmaceutical ingredients are incredibly tight. You even have to have a defined crystal morphology. There are great pharmaceutical firms in China that can do the job, but the kind of bulk producers who crank out 3BP for 125USD/ton aren't equipped to do it. There's a lot of competition and a free market in cars, for example, but I can't get that Tesla I want for five hundred bucks. *							Report ===							 #102					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 11:17 PM
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The toxicity issue regarding 3-BP appears to be well considered in the patent and in the human report. When given in the range indicated for therapeutic use 3-BP

did not appear to be toxic.

The main question that I am still unsure about is whether 3-BP is intended for systemic use. The patent and other sources seem unclear about this. There are many anti-cancer drugs that are effective when directly injected into a tumor. What patients really need is a systemically active treatment that could treat widely dispersed mets.

The metastatic melanoma patient report hinted that 3-BP would be effective as a systemic treatment. The patient was treated with an IV infusion of 3-BP.

It would be important to know whether either of the reported patients had wide spread metastatic illness. Perhaps these patients were selected on the basis of having huge tumor burdens that somehow were highly localized (for example, no brain mets etc.). *							Report ===							 #103					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 11:26 PM
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mag1, on 06 Feb 2015 - 11:58 PM, said:

You should work in marketing. Read your own rat study, which you quoted here:

http://www.longecity...e-3#entry712248

"In order to determine the therapeutic dose of 3-bromopyruvate for intravenous (FV) administration, a dose-escalation study was conducted in normal Lewis rats (non-tumor bearing). Each group of animals (6 rats per group) received incremental doses of 3- bromopyruvate intravenously (2.5mL of 5, 10, 15, 20, 25 and 5OmM 3-bromopyruvate). The animals were observed for a period of 3 weeks and watched for any evidence of toxicity. The therapeutic dose was found to be 2OmM. At the highest dose of 5OmM, all the animals in the group died within 15 minutes. "

So in order to determine the "therapeutic dose" they tested different doses. Only after scaling the dose were they able to look back at the results and determine the therapeutic dose!!! That is all hindsight, not foresight. It was even more interesting in the rabbit study that you quoted in that same post, where "it was observed that the 5mM concentration of 3-bromopyruvate completely destroyed the tumor, but also caused widespread necrosis of the surrounding healthy liver resulting in the death of all the rabbits within the group."

Where has that scaled dosing procedure been done on human beings? It has not been done, right? The German cancer study was n=1. Therefore we do not know if the doses used on that 16 year old boy were the rabbit equivalent of 2.5 or 5mM concentrations. Therefore, it is impossible to know exactly what is a therapeutic dose for a human, and it is also impossible to say that the dose used on that boy did not kill healthy liver cells.

You don't need to defend the German doctors. It was a heroic effort to save a human life on a new therapy for which there are no human guidelines. The boy would have died sooner without the therapy. Edited by pone11, 06 February 2015 - 11:27 PM. *                               						*							Report ===							 #104					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 11:29 PM
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niner, on 07 Feb 2015 - 12:03 AM, said:

I understand but a qualified company in the US buys the pharmaceutical grade from China, then tests for heavy metals, other contaminants, tests the concentration and purity, etc.   Lousy manufacturers with a decent process and heavy quality assurance from a party who won't pass subgrade product can go far.

Once any chemical gets to this level of manufacturing volume, I think it is very very hard to control capitalism doing what capitalism always does:  increase supply and decrease prices, under relentless competition. *							Report ===							 #105					niner ===			*			Member, Moderator *15,386 posts *	3,273 ₮			*							Location:Philadelphia Posted 06 February 2015 - 11:30 PM
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Well, if it's really non-toxic at therapeutic levels, then it should be perfect for systemic use. Toxicity is usually the dose-limiting effect in cancer therapy. *							Report ===							 #106					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 11:42 PM
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Example 24 was trying to find the maximal dose. The patent has extensive documentation.

For example, in  Example 17  Direct Intraarterial Injection of 3-BrPA into Liver Implanted VX2 Tumors Selectively Inhibits the Viability of Cells Therein without Altering the Viability of Surrounding Liver Tissue:

"...Animals treated identically, but not receiving 3-BrPA served as controls. Optimal results were obtained by delivering 25 ml 0.5 mM 3-BrPA, waiting 4 days, and then excising and subjecting each tumor, and the surrounding liver tissue, to histological analysis. The results obtained from this novel approach proved to be quite dramatic.

Compared to control "untreated" tumors, where representative sections (7 slides/tumor) obtained outside the central core region revealed nearly 100 % viable cells (Figure 2C), similarly located sections obtained from tumors treated with 3-BrPA (Figure 2D) contained almost all non- viable cells (nearly 100 % necrosis)."

This is a direct injection model. the dose used here was 25 ml 0.5 mM 3-BrPA. In the maximal dosing used in example 24, a 2.5 ml dose of 50mM was used which is 10 times higher than that used in example 17. It is known that at doses beyond the therapeutically intended range 3-BP would have serious toxicity. However, after receiving 9 treatments over a period of almost 1 year, the German patient had not demonstrated any toxicity. The scans shown in Figure 4 do not show evidence of such toxicity. The article noted that the liver was continuing to regenerate. The patient appeared happy and healthy on his birthday. *							Report ===							 #107					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 06 February 2015 - 11:49 PM
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mag1, on 07 Feb 2015 - 12:42 AM, said:

But the actual dose calibration was in animals, and the dose for a human was an extrapolation from that. It's not the same as testing different doses in actual humans, and using statistics on a larger sample. I'm not saying you have to do that. I'm all for n=1. I'm all for dirty data. I'm saying you cannot rule out that they dosed too high and killed normal liver cells.

The point they make about not showing any toxicity is interesting, but this is their characterization. Toward the end they did find ascites, and there is no way to prove if these came from dead cancer cells or dead "normal" liver cells.

It is really remarkable that after nine treatments they claim no toxicity, but suddenly after one dose there is lethal toxicity? Either something doesn't add up there, or maybe the dose toxicity shifts over time as the primary cancer dies off. It looks like a tricky business. *							Report ===							 #108					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 06 February 2015 - 11:56 PM
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The patent is quoting state of the art treatment with 3-BP as of December 2006. Concerns about toxicity from 3-BP have been addressed by subsequent research.

For example, the website of the company seeking to commercialize 3-BP notes the below research. Such research might help make 3-BP a patentable drug.

Clin Cancer Res. 2014 Dec 15;20(24):6406-17. doi: 10.1158/1078-0432.CCR-14-1271. Epub 2014 Oct 17. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer.

"...In vivo, animals treated with β-CD-3-BrPA demonstrated minimal or no tumor  progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the β-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for β-CD-3-BrPA. CONCLUSION:

The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered."							 Edited by mag1, 07 February 2015 - 12:24 AM. 						* Quote						*							Report ===							 #109					pone11 										===			*			Member                          		*488 posts		*	112 ₮			*							Location:Western US						*							no					Posted 07 February 2015 - 12:05 AM
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mag1, on 07 Feb 2015 - 12:56 AM, said:

We were talking about establishing therapeutic dosing for generic 3BP. Now you change the topic to a proprietary version of 3BP. That's not the conversation we were having. *							Report ===							 #110					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 12:12 AM
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True, but different formulations of 3-BP have been in development for quite some time. Straight 3-BP is now 15 years old! The research into 3-BP since then has found even better formulations combinations etc.

The encapsulated form of 3-BP noted in the article does not appear to require much technical expertise to prepare. It never seemed likely that a straight 3-BP product would be marketed.

Perhaps they will put it into minicells!

In addition to reformulations of 3BP there are also combinations which would allow for lower dosing of 3-BP (butyrate etc.). *							Report ===							 #111					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 07 February 2015 - 11:31 AM

It disturbs me that the therapeutic dose in rodents was found to be 20 mM, whereas 50 mM was rapidly fatal. That's a thin margin of safety -- so thin that we might need to abandon the concept of dose altogether, in favor of continual patient monitoring during administration.

Then we have this issue of killing -- or not -- the surrounding healthy cells. Let's not confuse implanted vs. native tumors: the latter should have more precancerous cells surrounding them, due to the spatially continuous evolution of the tumor in situ. This could explain some of the contradictions between having no effect on healthy cells vs. killing the patient due to excessive "normal" cell death. (I use quotes because I suspect that these cells were actually partially glycolytic.)

I don't think it's bad that 3BP might kill these "swing cells", on their way to becoming cancer but not yet detectable as such. Again, it needs to come down to continual patient monitoring during administration.

"They will all struggle to manufacturer 'studies' that show that 3BP + <insert-poison-here> is 5% more effective than 3BP alone, and then use that fact to justify charging $100K more for the therapy." That would be hilarious, were it not so accurate. But this is the difference between Big Pharma and Big Pseudoscience: whereas Big Pharma overcharges for usally-trivial patentable differences in clinical outcome, Big Pseudoscience provides the most tested primal forms of the therapies, but is agnostic to evidence of efficacy and overcharges for the artisanal factor (e.g. soothing personal attention, aromatherapy in the lobby, organic juices, etc., hence the $28K). But at least we have a choice, and in this case, Big Pseudoscience is providing better options at present. International competition will certainly help.

@pone11: I would support your creation of a "lysis cancer scanner" thread, even if it only sits idle until its value and relevance become obvious years hence. It's too good an idea to get lost here. As to all this tracking business, I propose a Cancer section, which in comparison to "Medicines & Diseases" (its parent) is actually a narrowly focussed topic. I've proposed this before.

I definitely would keep this thrad on 3BP alone. The existence of a Cancer section would draw the experts and critical thinkers that we need for potential breakthroughs of this magnitude, without muddying this thread, which is justifiably complex as it is.

If it helps, we could even have 2 subfolders: "Tumor-Specific Therapy" and "Broad-Based Therapy", or something more simply worded. *							Report ===							 #112					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 01:01 PM
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The questions raised on the thread about toxicity are important. However, it should be understood that the patent is a highly detailed description of many instances of the use of 3-BP at many dosage ranges and with varying purposes in regard to describing aspects of treatment. After reading the patent in its entirety one realizes how non-toxic 3-BP treatment is when used in the manner described at the indicated therapeutic dosages for the selected purposes.

It should be noted that in the below quote they are using 0.5 mM of 3-BP. In other parts of the patent they use 20, 25, and up to 50 mM 3-BP (that is the molarity used was up to 100 times higher). Yet, it needs to be clearly understood that the patent is describing various methods and dosages that are not directly comparable. For instance, the 2.5 ml of 20 mM 3-BP in example 24 was in the context of intravenous administration of the drug. Toxicity arose from this dosage scheme.

However, in example 17, 25 ml of .5 mM 3-BP injected intraarterially had a dramatic treatment effect with no detectable toxicity. It should be understood that directly targeting liver tumors in this way would presumably not expose other organs to the risk of toxicity arising from 3-BP treatment. In such a procedure there might be a method of actively diluting the 3-BP at the end of treatment, in order that no other organ would be exposed to concentrated 3-BP. Yet, once the blood supply was reopened rapid dilution would occur spontaneously once the 3-BP mixed with the blood. The so called TACE procedure (direct targeting of the liver) was used in the German report.

For Example,

"Example 17: Direct Intraarterial Injection of 3-BrPA into Liver Implanted VX2 Tumors Selectively Inhibits the Viability of Cells Therein without Altering the Viability of Surrounding Liver Tissue.

To test our hypothesis that direct intraarterial injection of a potent inhibitor of cell ATP production (3-BrPA) may selectively inhibit the viability of cells within the tumor, we employed the established VX2 tumor model for reasons described above. Small chunks of a donor VX2 tumor were minced, surgically implanted in the livers of 6 rabbits/experiment, and allowed to grow for 14 days (Figure 2A). At this time, the single well- delineated tumor that developed in each liver exhibited a high degree of arterial vascularization due to the onset of angiogenesis. After fasting the animals for 24 hours and administering anesthesia, a catheter was carefully inserted into the femoral artery and guided by fluoroscopy into the hepatic artery to a position near the tumor site (Figure 2B). Then, a single bolus injection of 3-BrPA was delivered in about 2 min directly into the artery. Animals treated identically, but not receiving 3-BrPA served as controls. Optimal results were obtained by delivering 25 ml 0.5 mM 3-BrPA, waiting 4 days, and then excising and subjecting each tumor, and the surrounding liver tissue, to histological analysis. The results obtained from this novel approach proved to be quite dramatic.

Compared to control "untreated" tumors, where representative sections (7 slides/tumor) obtained outside the central core region revealed nearly 100 % viable cells (Figure 2C), similarly located sections obtained from tumors treated with 3-BrPA (Figure 2D) contained almost all non- viable cells (nearly 100 % necrosis). Viable tumor cells were detected only in small areas near arteries feeding the tumors (Figure 2E), and at the tumor periphery where sinusoidal blood is available. This may reflect more active mitochondria in these oxygen rich environments that are not completely debilitated at the concentrations of 3- BrPA used. Significantly, no damage occurred to liver tissue surrounding tumors that had been treated with 3-BrPA (Figures 2F and 2G). These results, reproduced in a number of experiments, were subjected to statistical evaluation. Tumors untreated with 3-BrPA (controls) contain 74 ± 5% viable cells in the entire population (Figure 2H, 1st column). The remaining cells, located within the hypoxic tumor core, have already become non-viable, a common feature of rapidly growing solid tumors. Treatment with a single intraarterial injection of 3-BrPA decreases the number of viable cells to 16 ± 5% (Figure 2H, 2nd column), thus increasing the total number of nonviable cells in the population to 84 ± 5% (P< 0.05). The maximal number of non-viable cells observed in any one experiment was 90%. In sharp contrast, the surrounding liver tissue remained completely viable in all cases examined (Figure 2H, 3rd and 4th columns)." 						*							Report ===							 #113					mag1 										===			*			Registered User                         		*228 posts		*	104 ₮			*							Location:virtual					Posted 07 February 2015 - 02:51 PM
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The treatment with 3-BP in the German report did not appear to result in observable direct liver toxicity. Throughout the article statements by the authors make clear strong claims of the safety and non-toxicity of 3-BP when used in this human patient at the dosage indicated and with the particular method of administration used.

For example,

In the Introduction, "In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells"

In the Conclusion, "A patented and proprietary formulation of 3BP is safe at the concentrations (2–3.5 mg/kg body weight) employed for TACE delivery in humans. No major cyto-toxicities of this specially formulated 3BP have been observed. Please note that unformulated 3BP may be harmful in some cases."

"Liver regeneration is not inhibited by 3BP treatment."

While further noting,

"Careful monitoring of blood ammonia, uric acid, and urea levels is paramount during 3BP treatment."

"The levels of albumin and billirubins are also important parameters in assessing liver functions and in predicting a patient’s survival during 3BP treatment."

These statements by a team of medical experts should not be dismissed lightly. As their claims are based on very comprehensive monitoring of the patient. The researchers carefully monitored a variety of measurements that would indicate liver toxicity:

"at first presentation and his blood chemistry revealed high values of the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT), indicating liver abnormality / damage. "

[This liver damage was before the start of 3-BP treatment. They also performed a pre-3BP liver biopsy, MRI, CT, echo imaging, and PET scan.) Additionally, they monitored ammonia, uric acid and urea levels.

Furthermore, the article notes that the nature of the TLS in this instance presented atypically. This discrepancy in TLS might possibly offer insight into the patient's demise. If the widely accepted indicators of TLS "uric acid, potassium, and phosphorus in other cancers." did not apply in the patient's particular form of liver cancer (FLC), they might have been targeting the treatment response to the wrong biomarker.

"As indicated in Fig. 3b, ammonia levels fluctuated more than those of urea and uric acid during 3BP treatment. This is very interesting as FLC is eosinophilic which is indicative of a higher content of cellular protein than of nucleic acids. Therefore, it is suggested that the rise in blood ammonia following 3BP treatment was due to FLC cell death, releasing considerable amounts of cellular proteins. This elevation of blood ammonia may be characteristic of TLS of FLC as TLS is generally diagnosed by acute elevations of uric acid, potassium, and phosphorus in other cancers."

The significance of urea level measurement is revealed in the below quote.

"The urea level was low (Fig. 3b, pink graph),an average of 5 mM, indicating a still functioning nitrogen detoxification of the liver and kidneys."

It is fair to say that the patient received a very high standard of care.

Further, since this is the initial landmark case of 3-BP treatment in humans, it would be expected that if the treatment were found in some way to have been deficient, then it likely would not have been published. There might have been patients treated with 3-BP who did not have such a dramatic success as the German report. Such negative patient reports have not been published.

Toxicity of 3-BP treatment would likely be obvious, immediate and cumulative. In the animal studies, the toxicity caused by 3-BP was measurable within days (or a week or two of treatment(in some instances after a single injection)). 3-BP shuts down cellular respiration within minutes, and then rapidly degrades in the body. Any damage from treatment would occur quickly. In the human report, large initial doses were used and then the treatment was gradually scaled back. After a year of such treatment, any toxicity from 3-BP should have been observable. Toxicity would be expected through time to deplete the patient. However, the patient report describes a patient who during the year of treatment appeared to be progressively recovering. The one notable mention of liver toxicity in the report was toxicity existing prior to the start of 3-BP treatment (possibly caused by the tumor or the other chemotherapeutic drugs). *							Report ===							 #114					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 03:11 PM
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The question of toxicity has diverted attention from my main concern about 3-BP treatment, namely the range of cancers which 3-BP could be used to treat.

The 3-BP patent that we have been considering regarding the toxicity of 3-BP is mostly concerned with intra-arterial administration of 3-BP to liver cancers. This is a highly specific cancer indication. Much of the patent is not making wide ranging claims that 3-BP could safely treat all cancers. Shutting off the blood supply to the liver and directly injecting 3-BP into an occluded artery avoids exposing other organs to toxicity and maximizes the potential of success of 3-BP treatment. This so called TACE procedure was the method of 3-BP in the German report. The positive results noted with 3-BP in intra-arterial administration to the liver might have no application to a broader range of cancers.

Safe and effective 3-BP treatment of patients with widespread metastatic illness would be the real breakthrough. It is not clear whether such a human patient report has yet been published. *							Report ===							 #115					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 07 February 2015 - 03:13 PM
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resveratrol_guy, on 07 Feb 2015 - 12:31 PM, said:

This is exactly the right point:  even once you establish a therapeutic dose, you have to continually monitor for lysis and tissue death, and then you need to adjust dose and spacing.

What I don't understand is how do you monitor for death of healthy tissue? In case of the liver patient, they had liver markers that were going bad at the end of treatment. I guess we lost an opportunity there to see how adjusting the dose down might have improved outcome. It's also very bad that they didn't autopsy his liver and try to determine if there was necrosis of healthy tissue. *							Report ===							 #116					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 07 February 2015 - 03:15 PM
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mag1, on 07 Feb 2015 - 2:01 PM, said:

Implanted tumors are a bad model to use to determine the amount of damage done to "normal" cells around the cancer. The cancer has not had time to integrate completely into tissues the way a naturally occurring tumor does. *							Report ===							 #117					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 03:21 PM
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In the article,

Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP

Biochemical and Biophysical Research Communications 324 (2004) 269–275

Figure 1C shows that a dosage of up to 0.06 mM 3-BP had no effect on cell viability of normal hepatocytes, whereas at 0.03 - 0.06 mM 3-BP there was 90% tumor cell destruction. All the animals in the article receiving direct injections of 3-BP recovered. *							Report ===							 #118					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 07 February 2015 - 03:25 PM
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mag1, on 07 Feb 2015 - 3:51 PM, said:

You already posted all of this and we responded to it. Rather than responding to the issues we raised, you just repost the same facts again. Why do that? That doesn't improve a thread to have you ignore points other people make and just repeat things. You are just making the thread unnecessarily longer without adding content.

I responded to these facts here:

http://www.longecity...ndpost&p=712283

We have no human studies to determine therapeutic doses. Therefore we have no way to know if the dose the German boy was destroying healthy tissue in addition to cancerous tissue. The fact that the doctors deny this isn't proof that it is so. There was no autopsy on the liver.

I suppose that 3BP could have one safe dose at the beginning, and then maybe there is some accumulative effect that requires dose adjustment later. All of that has yet to be figured out. Edited by pone11, 07 February 2015 - 03:26 PM. *                               						*							Report ===							 #119					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 07 February 2015 - 03:38 PM
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mag1, on 07 Feb 2015 - 4:21 PM, said:

Can you start publishing full text links to your studies? It really helps people out, and this thread has value for people so maintaining quality is important. Full text to your study is here:

http://www.sciencedi...006291X04020625

It looks like these were subcutaneous tumors. They were therefore not well integrated into vital organs of the body.

That would be a poor model for evaluating how 3BP might kill "normal" cells that are adjacent to a cancer. As resveratrol_guy correctly points out, many of those "normal" cells are probably in some pre-cancerous state and have been made glycolytic, thus subject to the actions of 3BP. So treating something like a late stage liver cancer becomes extremely treacherous.

Rather than reflexively posting every study with a "therapeutic" dose, you should acknowledge the rabbit and mouse studies you posted, referenced in my post here:

http://www.longecity...e-4#entry712283

This finding that there are doses of 3BP that kill "normal" cells adjacent to a cancer is important. You shouldn't keep trying to bury it. Rather we should acknowledge:

1) We don't know the full extent of dose toxicity in humans, yet.

2) This toxicity on adjacent cells may be different:

a) in different cancers

b) in different stages of a cancer

c) in different patients based on biology

I think resveratrol_guy made the right point:  we need to develop methods for evaluating when this necrosis of "normal" tissue is happening, and the dose or spacing then needs adjustment. The point is ANY dose that remains fixed is probably the wrong approach. Rather, this is a drug that requires a very interactive methodology:  adjusting dose to the toxic effects measured after administering a dose.

My question is how would you do this in a liver cancer? Would it require you to constantly take biopsies of the liver tissue? That hardly seems practical, and it would probably be pretty dangerous if repeated too often. Edited by pone11, 07 February 2015 - 03:41 PM. *                           Good Point x 1 *							Report ===						sponsored ad					=== *			Advert Advert:
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===							 #120					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 03:57 PM I am becoming somewhat confused by the argument.

The noted quote from the patent used dosages of 20mM and 50mM etc. intravenously.

The German patient received intra-arterial treatment. The description in the patent did not find toxicity in animals when they were treated with 3-BP using the optimal intra-arterial liver protocol.

"Rabbits treated with 25mL of 1.75 mM 3-bromopyruvate had 100% tumor cell destruction without any damage to the normal liver"

The medical experts in the German report used a wide range of biomarkers to assess liver toxicity. Liver toxicity was not found. In light of the evidence presented in the article, I do not understand why the possibility of liver toxicity continues to be suggested.

In fact, the article notes "Regeneration of liver tissue was also observed and the data are being analyzed for future publication." The authors claim they have direct evidence that the liver was recovering and perhaps they could also show that 3-BP treatment did not cause toxicity. Liver biopsy likely was performed during 3-BP treatment (as might be expected).

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175 replies to this topic ===							 #121					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 04:22 PM

Something else should be mentioned.

When the doctors began treatment with 3-BP, they immediately pushed a bolus dose over a few minutes intra-arterially. The first day's dose was a total of 250 mg.

The obvious question is: How did they know such a dose was safe?

At the wrong dose 3-BP would quickly kill a patient. They seemed pretty confident that this would be safe. If I had been the doctor involved in the care of the patient, I would not have done a rapid bolus push of 3-BP without knowing whether or not it was safe.

The suspicion is that other patients had already been quietly treated with 3-BP. This would not be entirely unexpected. There are large numbers of available end stage cancer patients. Under German law, doctors are allowed to use their professional judgement in choosing treatments.

If this were in fact correct, then patients with severe illness might have been treated and the toxicity (or lack thereof) of 3-BP treatment would already have been known before treatment began with the German patient. *							Report ===							 #122					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 04:55 PM
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The melanoma report adds a different perspective on 3-BP treatment.

http://www.ncbi.nlm....les/PMC4110469/

The article presents evidence that this patient did not experience toxicity due to 3-BP treatment. The article notes that on the basis of serum ALT, AST, total bilirubin, albumin, etc. renal and liver function was determined to be normal.

There are a few interesting aspects of this patient report that should be noted.

The patient was treated with IV 3-BP. This is important as it indicates that 3-BP might be used safely to treat widespread illness.

Eight IV treatments of 3-BP (between 1 and 2.2 mg per kg) did not result in detectable toxicity. However, there was also no great therapeutic effect either. When paracetamol was combined with 3-BP, a massive anti-tumor effect was seen immediately.

Paracetamol might allow for a minimal exposure to 3-BP. Combination treatment could allow for extreme responses without heavy repeated doses of 3-BP. *							Report ===						sponsored ad					=== *			Advert Advert:
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===							 #123					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 07 February 2015 - 04:57 PM

mag1, on 07 Feb 2015 - 4:57 PM, said:

I'm also confused. You selectively quote just the things that make your initial point that there is no toxicity, and you selectively do not quote from your own sources - and ignore posts of others - showing that there is probably destruction of adjacent "normal" cells at some dose.

I don't think we are going to resolve this. It appears to just be your style to keep repeating the same studies and ignore the points other people make. *							Report ===							 #124					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 05:32 PM
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The toxicity concerns raised on this thread have been the focus of ongoing 3-BP research. Over the last 15 years improvements have been developed. The microencapsulation of 3-BP and the combination with paracetamol were ways of minimizing 3-BP exposure while maximizing therapeutic results.

The results with paracetamol in the melanoma patient were especially noteworthy. Using 2.2 mg/kg injected IV, along with paracetamol, the metastatic melanoma patient had a massive anti-tumor response. This is somewhat surprising as this was an intravenous dose. It spread through the patient's body and yet was still effective. Very impressive. The German report used a dosing of 2-3.5 mg/kg for TACE delivery. This would appear to be a very large dose, delivered to a small volume in comparison to the metastatic melanoma patient.

Perhaps the dosing in the liver cancer patient could have been substantially lower with combination treatment of paracetamol. This would have greatly helped in reducing concerns of 3-BP toxicity. Smaller and fewer doses of 3-BP could then have been used. *							Report ===							 #125					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 07 February 2015 - 08:14 PM
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Wow, synergistic combination effect of rapamycin and 3-BP. Synergistic as in multiplicative benefit.

Anyone have the numbers? How much of a multiplicative effect?

No liver toxicity found in mouse models of lung cancer prevention using aerosol delivery of both drugs.

Cancer Prev Res (Phila). 2015 Feb 2. pii: canprevres.0142.2014. [Epub ahead of print]

Enhanced Antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.

http://cancerprevent...PR-14-0142.long

*							Report ===							 #126					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 08 February 2015 - 02:30 AM
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mag1, on 07 Feb 2015 - 9:14 PM, said:

The abstract of your link is behind a paywall. Are you working in a healthcare environment that gives you access to that?

Here is the abstract of the study he was trying to post:

http://cancerprevent...R-14-0142.short *							Report ===							 #127					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 08 February 2015 - 11:34 AM
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I was not sure which url for the article to post.

The submission date on the article is a sobering reminder of how dated scientific research can be (even when it is hot off the press).

The posted article was submitted April 2014!

Scientific articles are carefully scrutinized before being sent for publication. How is such a delay justified?

Why doesn't the scientific publishing community publish "roughs" or "betas"? That is what is done with software.

The modifications made after the authors have sent it for publication likely would not be substantive.

The ethical implications of withholding medically relevant information from patients for such an extended period of time deserve careful contemplation.

It is not entirely clear whether the current publication practice complies with international law.

The quality of the scientific literature might even be enhanced if websites (perhaps even this one) or other reviewers provided commentaries

on the "roughs". Authors could then integrate such ideas into the final version of their article. Reviewers of such articles would be interested to know

which suggestions and critiques were deemed worthy of rebuttal by the authors.

This form of democratic peer review could greatly enhance the quality of research. Peer review probably often involves the input from a small group of like thinking individuals. Important questions and clarifications might never occur to such groups.

For example, in the article on the liver cancer patient it would surely be helpful if clarification had been provided surrounding the liver overload that occurred near the 10th treatment. Might the authors accept that too much 3-BP was given to the patient? *							Report ===							 #128					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 08 February 2015 - 12:33 PM

Perhaps we must accept the fact that monitoring for the destruction of normal cells as opposed to cancerous ones is intractable. (This is basically the limitation of the lysis scanner, not to mention every other known piece of medical technology which might safely be brought to bear on a living patient.)

But then, maybe we shouldn't be drawing this crisp distinction at all, because it seems to boil down to the percentage of glycolytic mitochondria in any given cell. In this sense, no autopsy as currently performed would determine the answer, either.

Fortunately, all this might not matter, to the extent that (1) we can monitor the patient and apply maximum therapy within safe limits and (2) we can, in rapid succession to 3BP, attempt to clean up the "crater" left by the necrotic cancer, and plant stem cells around its inner surface. For example, excise the necrotic "carcass" of a post-3BP liver tumor using positive margin, then spray stem cells all over the inside walls of the hole left behind, which would now consist of mostly healthy cells. It would be like digging up the soil under a former toxic waste site, to a depth of 1 meter below the lowest known level of pollution, then planting food crops on the exposed clean soil.

As to paracetamol, I also wonder if we're just assuming that its synergism is due to glutathione suppression, which in principle could cause energy-starved cancer cells to die of routine oxidative stress which cannot be healed promptly. But this might not be what's happening at all. Maybe it's some other effect of paracetamol entirely. Either way, it needs more experimentation (just like rapamycin and salinomycin) so as mag1 suggested, we can minimize 3BP dosage.

If you want to get ahead of peer review, which suffers some obvious disadvantages as pointed out above, try arxiv.org, which is the world's preprint junk pile. The only thing that peer review accomplishes is to reduce the error rate. That's great, in and of itself, but it must be weighed against the time consumed by doing so. My strong suspicion is that we're better off studying half-baked preprints months before their polished counterparts emerge in publications, many of which end up getting retracted anyway. Of course, patients need to be informed as to the therapist's statistical basis of confidence in any given therapy, which is likely to be weak if the only source was preprint papers. Edited by resveratrol_guy, 08 February 2015 - 12:35 PM. *                               						*							Report ===							 #129					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 08 February 2015 - 01:22 PM
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This is great, the people are coming back! I was worried there was a mutiny afoot. This topic is too important to be derailed. 3-BP still appears impressive (especially if the toxicity issues are manageable). I will try harder to be more responsive.

I do not think that I could ethically accept the proposition that any research results with medically relevant importance to patients that I might discover would be embargoed for a up to a year or more.

Consider the timeline for the liver cancer patient.

-2008: presented at a hospital,

-2008: US 3-BP researchers contacted

-January 26,2009: the first TACE treatment was performed

-February 26,2009: first day of treatment with 3-BP administered by TACE

-February 26,2009 6:00PM: patient leaves the hospital after recovery period

-March 10,2009 (approximately): patient receives another treatment of 3-BP

-March 14,2009 (approximately): patient hospitalized with hepatic coma. This is usually fatal.

-March 14,2009 (approximately): patient returns home and recovers.

-March-November 2009: patient receives 8 more rounds of 3-BP treatment

-December 9,2009: patient succumbs to reported liver overload

-January 9,2012: article received by journal -January 14,2012: article accepted by journal -February 11,2012: article published online

Well over ten million people died from cancer while this article made its way to publication.

It might not have been unreasonable to have held a news conference in March of 2009 to disclose the startling results that had been achieved even at that point. I would have. It could have then been reported that 3-BP had been safely administered three times and a huge anti-tumor response resulting in TLS occurred on the third treatment.

I do not understand how criminal and civil consequences do not apply for the non-disclosure of such medically relevant findings. Did not the ethics committee find this ethically unacceptable? How can international law be ignored in such instances?

Now in 2015, all these years later, we are still trying to fully understand the results from 2009. With timely disclosure of the initial results, current research would be years further ahead. *							Report ===							 #130					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 08 February 2015 - 01:53 PM
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Searched arxiv.org.

No results from a search of 3-Bromopyruvate,or 3-BP.

However, the term cancer produced a little over 300 matches. *							Report ===							 #131					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 08 February 2015 - 03:43 PM
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I am not especially informed about the questions of toxicity, though many current technologies could give some indication of such concerns. For example, the LDH measure gives a reasonably accurate means for assessing whole body tumor burden. This was the primary efficacy biomarker used with the metastatic melanoma patient. The liver cancer report noted that a widely used cancer diagnostic technology is PET scanning which actually is based on overexpression of Hexokinase 2 (from the glycolysis pathway [note relation to 3-BP mechanism]).

The CT scans in Figure 4 of the liver cancer report appear to show the liver tumors. There is some uncertainty as to whether the scan is able to detect liver tumors after 3-BP treatment (due to not using Lipiodol). It is not mentioned in the article whether liver toxicity could be established by simply studying these scans.

It is possible that the liver was chosen as the first test of 3-BP due to its regenerative ability. The article noted that the patient's liver was regenerating and they intended to publish these results.

In the animal studies using direct intra-arterial treatment of the liver, there did not appear to be any toxicity at optimal dosing and method of dosing and no restorative post-treatment was necessary.

We still do not have a good sense of long term safety with IV dosing. The investigators seemed to be quite cautious about systemic dosing even at 1 mg per kg with the melanoma patient. A longer term of observation of this patient would have greatly helped us understand such risk of toxicity. IV dosing would expose all the organs of the body to 3-BP. It would also be very helpful to know whether the paracetamol - 3BP combination is broadly effective in cancer patients.

This is all the more frustrating as articles reporting patients with earlier stage cancer treated with 3-BP have not yet been published. Treating patients before they developed unsustainable tumor masses would reduce the risk and increase the effectiveness of 3-BP treatment. *							Report ===							 #132					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 08 February 2015 - 04:03 PM
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It has been an ongoing mystery in the scientific community as to why 3-BP does not appear to be more toxic to organs than has been to this point demonstrated. 3-BP is an alkylating agent which would be expected to cause substantial problems associated with toxicity.

The below article explains that the subdued organic toxicity effects of 3-BP at 1.75 mM in rats when given systematically was apparently due to 3-BP binding to serum proteins.

http://www.pubfacts.... in a rat model. *							Report ===							 #133					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 08 February 2015 - 04:30 PM
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On a closer examination of the above article, it is not clear how the irreversible binding of 3-BP by serum proteins would not also prevent 3-BP from having an effect on the cancer.

It would seem that such a binding might result in a non-toxic, though ineffective drug. (The binding occurs rapidly as noted in the article). However, this is inconsistent with the effectiveness shown with systematic administration in the metastatic melanoma patient.

"As our findings demonstrate the interaction of 3-BrPA with serum proteins, it is likely that the particular interacting 3-BrPA molecule will no longer be available for further alkylation or toxicity. Further, owing to the irreversible alkylating property of 3-BrPA, it is unlikely that the 3-BrPA might be released from these proteins at later stages to contribute any toxicity." *							Report ===							 #134					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 08 February 2015 - 04:33 PM
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resveratrol_guy, on 08 Feb 2015 - 1:33 PM, said:

I thought that cancer cells show distinct changes to mitochondria. Specifically the inner folds and membrane of the mitochondria in cancer disintegrates, and the mitochondria becomes a glycolysis factory. Since the inner mitochondrial membrane is where aerobic metabolism and the electron transport chain reside, I guess that makes some sense.

Someone correct me, but in an autopsy couldn't they sample many areas of tissue necrosis, then analyze the mitochondria of those dead cells, looking for the ones that show the telltale signs of cancerous changes? I'm sure there must be other biomarkers for cancer in the cell that could be tested as well? How much of this remains stable in the hours or days after death? *							Report ===							 #135					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 08 February 2015 - 08:01 PM

pone11, on 08 Feb 2015 - 5:33 PM, said:

There's no reason that couldn't be done. I believe you're referring to the cristae mentioned by D'Agostino, which are the interior of the external mitochondrial membranes. For that matter, the inner boundary membranes may decay as well. The problem, though, is that you have a huge tissue volume to biopsy. What are you going to do, sample a cell for every cubic centimeter, then put together a 3D heatmap showing the glycolytic percentage of each cell which survived (or did not survive) therapy? (And how could you ascertain which cells had survived, considering that the cells would overwhelmingly be dead by the time you do an autopsy?) This would be extremely useful data, but it seems very difficult to gather, unless perhaps we could use nuclear magnetic resonance. (Presumably glycolysis involves different ratios of carbon and other atoms as compared to OXPHOS. Resonating with the most popular nuclei in either case might show different intensity levels, allowing us to form a 3D heatmap without lifting a knife. This isn't new thinking; MRI uses hydrogen NMR on a routine basis.)

For that matter, why are we using hydrogen resonance with "receptor dyes" to attempt to image cancer? Why not use another form of NMR which looks for glycolysis? Kind of like PET minus the ionizing radiation. *							Report ===							 #136					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 08 February 2015 - 08:05 PM

mag1, on 08 Feb 2015 - 2:53 PM, said:

That's not good :(

Maybe it means that nothing's in the pipeline, at least from the usual institutions for biotech research.

Time for dirty data. *							Report ===							 #137					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 10 February 2015 - 05:57 PM
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PubMed has almost 20,000 articles listed for cancer in 2014.

arxiv.org appears to be weak in the medical sciences. *							Report ===							 #138					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 14 February 2015 - 08:09 PM
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User @resveratrol_guy asked me to document my idea to use 3-BP as a method to detect cancer in a new thread. Here is the thread:

http://www.longecity...ancer/?p=713709 *							Report ===							 #139					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 16 February 2015 - 11:05 PM

I just realized that 3BP might actually be the gateway to mundane stem cell therapy. Please let me explain.

The biggest problem with Aubrey DeGrey's "maintenance" approach to longevity is that, among other things, it presupposes that the availability of therapy (and money to pay for it) implies the willingness to avail oneself of it. But, cost issues aside, the first reaction that anyone seems to have to stem cell therapy in general is one of fear -- fear of cancer. I must admit, despite my clear understanding that there is a difference between angiogenesis (proOXPHOS) and patho angiogenesis (proglycolysis), the idea of jacking up my circulating stem cell population by something like an order of magnitude does actually drain the blood from my face. It takes guts (or insanity, in my case)!

What we need as a society is to transition to a world in which stem cell therapy is medically (and financially) mundane. Indeed, the cancer risk is not unrelated to the financial cost: imagine how much it costs to obtain general liability insurance for a stem cell therapy center, for instance.

3BP may be the answer. Here's my caveman rationale:

Stem cells in 2015 work like this:

1. Harvest from bone marrow, adipose tissue, or cord blood.

2. Centrifuge them for debris filtration (optional).

3. Reinject to target tissue (usually, general circulation or lumbar CSF).

Stem cells in 2035 may work like this:

1. Harvest from bone marrow, adipose tissue, or cord blood.

2. Centrifuge them for debris filtration (required by the Stem Cell Quackery Act of 2029).

3. Give the extracted cells a "Warburg bath": set the Warburg threshold to some comfortable value, then fry all the cells which exceed it with the implied dose of 3BP. But realize that because this is done in vitro, we're not giving in vivo tissues any education about 3BP at all! So any malignancies which might reside in the patient remain therapy-naive (nevermind the fact that 3BP may be very hard for cancer cells to evolve around, as it is). And we have a decent shot at achieving a total kill, because presumably any would-be glycopathological stem cells would have been hibernating (because presumably we would have noticed bone marrow cancer or adipose cancer), waiting to cause havoc upon release into circulation. So in order words, we have a few random glycopathological stem cells which just got out of bone marrow prison, so it's time to fry them before they upregulate pathoangiogenesis pursuant to patient reinjection.

4. Reinject to target tissue (via DMSO-modulated transdermal sonication because, hey, it's 2035 already).

Think about what this would mean, societally. We would transition from "OMG angiogenesis are you nuts?!" to "Which growth factors do I need for next week's triathlon?" Just the attitude shift would be a major step toward an Aubrey DeGrey world. *							Report ===							 #140					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 17 February 2015 - 06:23 PM
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If we're talking about 20 years forward, why not genetically engineer the stem cells so they can't become cancerous?

Apparently, some animal (and people) are genetically protected against cancer. Why not give the stem cells the same advantage.

Alternatively, an entirely novel cell surface receptor could be engineered into the stem cells. This might allow minicells to selectively enter these stem cells.

Or even a molecular computer could be added to the cells which could destroy the cells. if it were determined that the cells had become dysfunctional. *							Report ===							 #141					resveratrol_guy ===			*			Registered User *377 posts *	151 ₮
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Posted 17 February 2015 - 09:44 PM

mag1, on 17 Feb 2015 - 7:23 PM, said:

Well you raise a good point, provided that we can manage to (economically!) replace the patient's lousy mitochondria with those of some Olympic athlete with no familial history of cancer. The problem is that that might only be possible to do on a few cells at a time, considering the complexity of a manual (how could it be automated?) mtDNA transplant across 1000 mitochondria using a theoretical nanosyringe; in this case, the ensuing replication stress incurred by duplicating those cells to therapeutic quantities (perhaps 40 bifurcations) could be significant to the point of outweighing the value of the superior mtDNA in the first place. But yes, it just might work.

But I really like this "kill switch" idea! One could imagine a proprietary receptor (made my a nefarious multinational corporation, just like in the movies) dedicated to minicell binding in the event of a catastrophic failure (or, on the positive side, if we learn how to enhance them postimplantation). Then the aforementioned corporation learns how to use them to control people, and we have the basis of a scifi thriller...

I think you're talking 2060. A Warburg bath is simpler and dumber. *							Report ===							 #142					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 02 March 2015 - 08:17 PM
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I was expecting sooner or later someone might try this with 3-BP.

http://pubs.rsc.org/...63f?page=search[open access]

This could really push 3-BP treatment forward.

Figure 3 from the article is somewhat confusing (they do not appear to be using consistent units). However, targeted delivery seems to give at least 1 log benefit over straight 3-BP. The units used in Figure 3B are not consistent with Figure 3A. Also, it would be nice to have the direct comparison on Figure 3B between targeted delivery with and without laser treatment. It is hard to say but it appears that the laser amps up the effect above and beyond targeted delivery considerably.

Table 1 found that targeted delivery increases effectiveness by 20 times over straight 3-BP! *							Report ===							 #143					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 02 March 2015 - 09:53 PM
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The article does not seem to provide clear comparisons between the effectiveness of the various treatments with and without the laser.

In Figure 3B, 3-BP appears to be 3 log more effective in comparison to the same cell type (PC3) in Figure 3A. The units used in Figure 3B for the other treatments using laser light are not directly comparable to those in Figure 3A. However, if they matched the benefit seen with 3-BP, than there would be a substantial benefit of the nanoparticles with laser light over straight 3-BP.

The supplemental tables Figure S8c even suggests that NT-3BP-AuNP is more effective than T-3BP-AuNP. It is very impressive that 50% of the cells with NT-3-BP-AuNP appear to be end-stage necrosis.

http://www.rsc.org/s...c4sc01963f1.pdf *							Report ===							 #144					prophets ===			*			Member *1,828 posts *	239 ₮			*							Location:US Posted 02 March 2015 - 10:24 PM
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pone11, on 18 Jan 2015 - 5:55 PM, said:

I'm not sure if this has been discussed elsewhere in this thread, but I thought I'd just point out that the beta blocker Propranolol is a Hexokinase II inhibitor, interferes with glucose metabolism, and is widely seen and preventative for cancer. I believe this is due to it's Beta-2 andregenic blocking effects (it blocks both B1 and B2). Other selective B2 inhibitors probably have a similar effect.

I point this out for anyone who comes across this thread and is looking for some kind of drug (as maybe they are a cancer patient) and might have more interest in something that has already been safely taken by millions of people vs. something unknown and still in development.

See: Propranolol inhibits glucose metabolism and 18F-FDG uptake of breast cancer through posttranscriptional downregulation of hexokinase-2. *							Report ===							 #145					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 02 March 2015 - 10:27 PM
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There was some evidence that Propranolol helped in melanoma.

This might be another agent to combine with 3-BP to amp up effectiveness. *							Report ===							 #146					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 21 March 2015 - 10:03 PM
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Wow, X-Ray Photodynamic therapy. It's off-topic but worth it.

One dose of 0.5 Gy X-Rays eliminated tumors!

X-Rays can penetrate deeply into the body.

http://cen.acs.org/a...oparticle-Take *							Report ===							 #147					pone11 ===			*			Member *488 posts *	112 ₮			*							Location:Western US						*							no Posted 21 March 2015 - 10:16 PM
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prophets, on 02 Mar 2015 - 11:24 PM, said:

Nice study, but they lost some opportunities there to:

1) Tell us did propanolol have any value as a prophylactic to prevent getting the cancer in the first place?

2) Did propanolol extend lifespan in the mice who had cancer?						*							Report ===							 #148					prophets 										===			*			Member                         		*1,828 posts		*	239 ₮			*							Location:US					Posted 21 March 2015 - 10:46 PM
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pone11, on 21 Mar 2015 - 11:16 PM, said:

RE:

1)  I'm not well read enough to know where propanolol has primary preventative effects on cancer.  However, I've seen several papers showing that it is preventative for metastasis, often driven by norepinephrine.  By blocking B2 receptors (which some beta blockers like metoprolol do not accomplish), propranolol inhibits some forms of cancer from metastasizing elsewhere in the body.

Example:  Metastasis of prostate cancer via norepinephrine is prevented by propranolol. migration of pancreatic cancer via norepinephrine inhibited by propranolol.

2)  Given the above fact, #2 seems likely to be true (in some instances).  But, I'm not much of an expert on anything cancer related.						*							Report ===							 #149					pone11 										===			*			Member                         		*488 posts		*	112 ₮			*							Location:Western US						*							no					Posted 21 March 2015 - 10:58 PM
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prophets, on 21 Mar 2015 - 11:46 PM, said:

Given that metastasis result, why is the drug company marketing propranolol not selling it off-label to doctors as an adjunct to other cancer drugs? That seems like a huge market for them.

The point on 2) was why didn't the original mouse study try to measure that lifespan extension.						*							Report ===						sponsored ad					===			*			Advert 		Advert:
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===							 #150					mag1 ===			*			Registered User *228 posts *	104 ₮			*							Location:virtual Posted 22 March 2015 - 12:01 AM Propranolol is a generic drug. There is no money to be made from studying its anti-cancer properties (just like 3-BP).