Respectful Insolence

Vitamin C and cancer revisited

ResearchBlogging.orgIt’s been quite a while since I wrote about this topic, but, quite frankly, I didn’t think anything new was likely to come up that would interest me sufficiently to take it on again. I was almost right; it’s been well over two years since the last time I discussed the issue of whether or not vitamin C has any role in treating cancer.

When last I left the topic, two studies had been released that were being widely cited as a “vindication” of Linus Pauling. As you may recall, Pauling was the Nobel Laureate who succumbed to what’s sometimes called the “Nobel disease” in that he turned into a major crank late in his life. The main manifestation of his crank tendencies was his major role in the founding of the orthomolecular medicine movement. So-called “orthomolecular medicine” generally involves treating all disease with megadoses of various vitamins and other nutrients, chief among which was vitamin C, also known as ascorbic acid. Thanks largely to Pauling’s influence and the power and influence that come with his having been a two-time Nobel Laureate, the concept that megadoses of vitamin C could be used to treat diseases mild and serious, ranging from the common cold to cancer, has hung around far longer than it would likely have if it were judged on a strictly scientific basis. There are endless studies, some of which seem to show a benefit in preclinical models but only at enormous concentrations, and there are clinical studies that fall into two categories: flawed studies that seem to show a benefit (one of which Pauling himself inflicted on the medical literature) or better-designed studies that show no effect. All in all, I remain rather puzzled at the continued interest in vitamin C as some sort of cancer cure, given that the largest effects ever reported were in fact quite modest and given how huge the doses necessary to achieve even those modest responses in animal models had to be. The whole thing strikes me as the proverbial long run for a short slide. But apparently there are a lot of people who like getting their butts dirty sliding into base, because the attraction to vitamin C still lives on. Never mind that there are charges that Pauling could not abide negative data to the point of suppressing them or that there were also data that suggested that vitamin C may may stimulate the growth of some tumors in mice. To many in the world of “complementary and alternative medicine” (CAM), vitamin C at large doses remains a “natural” cure for what ails you.

Most recently, I deconstructed two studies. One study was of the dreaded “best case” series, a type of study I absolutely detest because it’s an excuse for purveyors of dubious therapies to cherry pick their “best cases,” even if it’s a handful out of hundreds or thousands, and this one was no different. Worse, even as “best cases,” these cases were not all that impressive as evidence for a therapeutic effect due to vitamin C. The other study, by Qi Chen, Mark Levine, and colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH was published in PNAS. Sadly, it wasn’t all that striking either, being only an in vitro study looking at the effect of very high concentrations of vitamin C on various tumor cell lines in cell culture. All I could do was to wonder was whether this study was evidence for clinically useful anti-tumor activity due to ascorbic acid or just another example demonstrating that it’s possible to kill tumor cells in vitro with almost anything if you jack the concentration high enough. I will admit that it was interesting that the vitamin C-mediated tumor cell killing depended upon the generation of H2O2 (peroxide) and could be abrogated by inhibitors of H2O2 generation. In any case, Levine’s conclusion was that vitamin C/ascorbate is a prodrug that results in the selective generation of H2O2 in tumor cells but not in whole blood. All in all it was a mildly interesting result, but hardly a stunning vindication of Linus Pauling.

Now, over two years later, Levine et al are back, this time with another study published in PNAS entitled Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. This time, they’ve done animal studies. Once again, these studies show mildly positive results. Once again, the whole endeavor strikes me as a long run for a short slide. Once again, I remain puzzled as to why there is such intense interest in what, even if it “works,” strikes me as a cumbersome and only mildly effective therapy.


Let’s look at the study itself. There’s one interesting thing that stands out right away when I look at it, and that’s that the manuscript was received for review on May 1 and accepted for publication on June 6. That’s incredibly fast, and it makes me think that this article was communicated, rather than submitted to peer review. (The manuscript lists the article as having been “edited” by Academy member Bruce Ames.) One thing that most people don’t understand about PNAS is that any member of the National Academy of Sciences can submit a manuscript and essentially choose its reviewers, whether that manuscript is by the member or “communicated” to the journal for another investigator. Indeed, getting a paper published in PNAS is quite easy for an Academy member and incredibly difficult for a non-member who does not have the connections that allow him to line up an Academy member willing to act as referee and thus is forced to submit his manuscript directly to the journal. On the other hand, PNAS used to be used more often that many would like to admit as a dumping ground by Academy members for their lesser work because of how easily they could publish in it. (Indeed, Linus Pauling first published his truly execrable retrospective and unrandomized “study” purporting to show that high dose vitamin C prolonged the lives of patients with advanced cancer in PNAS in the 1970s.) In recent years, fortunately, the journal has tightened up editorial standards and peer review considerably. I only mention all of this because it’s been a bit of a pet peeve of mine about PNAS, and, although the quality of published manuscripts in PNAS is generally high, stinkers do sometimes sneak their way in there, thanks to the lax peer review standards for Academy members, some of whom are occasionally tempted to abuse the privilege of being able to publish essentially anything they want or by the occasional Academy member who turns crank, as Linus Pauling did.

But I digress. Back to the meat of the science, so to speak.

Oddities specific to submitting manuscripts to PNAS aside, how good is the study? Answer: It’s OK but it’s nothing special. In fact, it’s not particularly “meaty,” with only four figures, one of which is essentially a rehash and extension of data from Levine’s previous PNAS paper. Indeed, if this paper were not about a controversial and questionable therapy that had been thought to have been found wanting and instead been about a new cancer chemotherapeutic, my guess is that this result would have been viewed as mildly promising but nothing earthshaking. However, it’s not about some new chemotherapy agent; it’s about vitamin C. Consequently, it got a fair amount of attention in the press last week. Basically, this study reports the results of in vivo experiments in mouse tumor models using high dose vitamin C to treat tumors. In the introduction, Levine argues that the reason previous studies using high dose vitamin C to treat cancer failed to show an antitumor effect was because the drug was administered orally. The body, he points out, keeps a pretty tight control over the allowable blood concentration of vitamin C, and it’s not possible to boost that concentration above a certain level with oral dosing alone. If the blood level of ascorbate could be boosted far beyond the limit that can be achieved with oral dosing, Levine hypothesized, it might reach concentrations in the millimolar range, which is the concentration range in which ascorbate has been shown to kill tumor cells in vitro.

The important thing to remember here, though, is that at these doses ascorbate is not acting as a nutrient. It is not a “nutritional” treatment for cancer, as some CAM advocates claim. Rather, it is acting as a drug. Indeed, these are doses that are many, many times greater than what is required for good nutrition; they are true megadoses. To illustrate the point, I note that the doses used in mice by Levine et al were on the order of up to 4 g/kg twice daily. Translating that dose to the proverbial 70 kg man would mean a dose of up to 560 g per day, or nearly a pound and a quarter, administered intravenously. Of course, mice are not humans, and, as it turns out, it doesn’t take doses quite that high to reach blood concentrations in humans as high as those achieved in the mice using 4 g/kg ascorbate (more on that later). Even so, we’re still talking huge doses of ascorbate just to get its blood and tissue concentrations into a theoretical potentially therapeutic range.

After in essence recapping results presented in Figure 1 of their previous study for this study again and adding more cell lines to the panel to show that high concentrations of ascorbate are selectively toxic to tumor cells compared to normal cells, Levine gets to the meat of his results by testing his vitamin C regimen in three different mouse models of cancer in athymic nude mice: Ovcar5, a human ovarian cancer cell line; Pan02, a mouse pancreatic cancer cell line; and 9L, a rat glioblastoma cell line. Why he chose these particular cell lines is not really explained clearly. Personally, if I were doing this experiment I would have used nothing but human tumor cell lines. Be that as it may, tumors were allowed to grow to a volume of 50 ± 10 mm3, at which point treatment with either intraperitoneal injections of ascorbate or saline placebo were commenced. The results are below:

i-e3db4c998eff1570ceed861d1f29aa89-figure1a.jpg

As you can see, the growth of the tumors is delayed, but there doesn’t appear to be any tumor shrinkage. This is actually not an uncommon result for a potential cancer chemotherapeutic drug (and, make no mistake, in this study ascorbate is being used as a chemotherapeutic agent); so I wouldn’t hold it against this study. Against these three cell lines, at least, ascorbate at these doses does appear to exhibit some in vivo antitumor activity. It’s modest and it requires massive doses producing high concentrations of ascorbate (millimolar range) in the blood to achieve, but it’s clearly there. At the end of the study, treated tumors were anywhere from 40-53% smaller than the untreated controls, and in the 9L cell line there was reportedly a major decrease in the frequency of detectable metastases.

The rest of the study involved mainly measuring the levels of H2O2 in the tissues of treated animals. Amazingly, peak levels of as high as 30 mM were obtained, which led the authors to reference a recently published phase I clinical trial of high dose intravenous vitamin C in advanced malignancy that shows that it is possible to approach such high concentrations of ascorbate in humans with doses of 1.5 g/kg. That’s still a lot but more achievable than 4 g/kg. Even so, it’s still problematic, as the infusion of high volumes of high osmolarity solution did cause problems in this trial. Nonetheless, if appropriate screening for conditions that might predispose to adverse events, even at the highest dose range, the results of the phase I clinical trial suggest that high dose intravenous vitamin C is fairly well tolerated.

Based on the animal studies and the safety data from the phase I trial, Levine concludes that high dose intravenous ascorbate represents a promising new therapy that should be further investigated. If his were the only evidence I saw being presented, I’d agree that it’s mildly to moderately promising as an anticancer therapy. However, I know the history of the use of vitamin C in cancer. More importantly, I know that the phase I clinical trial above did not identify a single patient with an objective response to therapy. True, the lack of even one objective response in a phase I trial does not necessarily mean that the drug doesn’t work, but it does dampen considerably optimism that it will work as a single agent. Taking the animal studies and the phase I trial together, I view the results with mild optimism that high dose vitamin C might have efficacy in human cancer. However, putting these results in context with what has been reported before over 30 years decreases even that mild enthusiasm, especially when coupled with my observation of just how modest the responses were in the mice and by just how much ascorbate was required to result in even a mild antitumor effect. Indeed, the authors of the phase I trial write:

In summary, this study shows that 1.5 g/kg ascorbic acid infused >90-120 min three times weekly is essentially free of risk and important side-effects when simple precautions are taken. In people with normal renal function, this dose achieves a plasma ascorbic acid concentration >10 mmol/l for several hours. No patient experienced an objective anticancer response, although two patients at the 0.6-g/kg dose received greater than six cycles of ascorbic acid with stable disease. Even though only six patients received the recommended phase II dose, our results suggest that the likelihood of an objective anticancer response to i.v. ascorbic acid alone is slight in unselected patients with multiply treated advanced cancer.

All of this brings up the question that just can’t be avoided: Does this study vindicate Linus Pauling and all the alternative practitioners of high dose vitamin C therapy for malignancy, such as the ones who treated Katie Wernecke for lymphoma? It depends on what you mean by “vindicate,” but my answer is: Not really, except perhaps in the weakest of ways, and here’s why. Remember, Linus Pauling didn’t claim that vitamin C in combination with other chemotherapeutic drugs might provide an additional incremental benefit to patients. That’s far too modest a claim. He said that “75% of all cancer can be prevented and cured by vitamin C alone.” Similarly, boosters of vitamin C as a cancer therapy don’t claim that it provides a small additional benefit when administered with chemotherapy, either. They claim that high dose vitamin C cures cancer at a high rate. Even the most optimistic appraisal of Levine’s results of Levine’s mouses study or the phase I clinical trial do not support any such claims.

The bottom line from my perspective: Yes, vitamin C probably has some antitumor activity for some tumors, but the word “underwhelming” comes to mind. Naturally, the authors of the phase I trial suggest using vitamin C in combination with chemotherapy, which is a perfectly reasonable approach for drugs that don’t show any objective evidence of activity as a single agent. However, this will not be easy, given that the sheer mass and volume of ascorbate that must be administered could easily interfere with other chemotherapy. One thing is fairly clear from the data known thus far: If high dose intravenous ascorbate has antitumor activity in humans, it is probably modest at best, and it definitely requires very high doses to achieve. High dose ascorbate might ultimately find its way into the armamentarium of science-based oncology, but it’s not likely to become a mainstay of treatment for any malignancy. It’s just too wimpy.

REFERENCES:

1. Chen, Q., Espey, M.G., Sun, A.Y., Pooput, C., Kirk, K.L., Krishna, M.C., Khosh, D.B., Drisko, J., Levine, M. (2008). From the Cover: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proceedings of the National Academy of Sciences, 105(32), 11105-11109. DOI: 10.1073/pnas.0804226105

2. Hoffer, L.J., Levine, M., Assouline, S., Melnychuk, D., Padayatty, S.J., Rosadiuk, K., Rousseau, C., Robitaille, L., Miller, W.H. (2008). Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Annals of Oncology DOI: 10.1093/annonc/mdn377

Comments

  1. #1 Kemist
    August 14, 2008

    Quircks of publication indeed.

    If *we* tried publishing with a molecule active at millimolar range in vitro, we’d be receiving a summary rejection even if our stuff was non-toxic. Indeed, we have a candidate molecule for leukemia that actually mildly stimulates the growth of normal lymphocytes while being toxic to HL60 in millimolar ranges. Still we don’t hold any strong hopes of publishing this in a high-end journal.

    millimolar ranges in vitro = waste basket for us. But we’re working with nasty synthetics from combinatorial chem :)

  2. #2 Phoenix Woman
    August 14, 2008

    If everything is all about “the wisdom of the body” for the CAM folk (I guess suffocation from massive histamine reaction is just peachy then, but I digress), then they should consider how the body fights to expel what it sees as excess levels of Vitamin C — which means that you can’t take enough C orally to even begin to fight tumors.

    Unless, of course, they switch to a homeopathic model. ;-)

  3. #3 Paul
    August 14, 2008

    Thanks Orac, that was a brilliant examination of a story that struck me as a little odd when I first saw it reported on the BBC.

    I suspected there might be some over-egging going on, and you’ve shown that they cooked up an omlette.

  4. #4 iznogud
    August 14, 2008

    Dear science blogger,

    The decontstructing in this article is “underwhelming”. Just to be brief about it, I don’t think “Scientists” who insult all those awful “CAM” “people” with decontructing results of the pro-vitamin studies, are doing something valuable to the science. What you do is nothing but a nice try to diminish some serious work. Surely Pauling was more a dreamer and far less scientist when orthomolecular movement comes to question, but please, if you don’t know how to explain the exact mechanism and have a precise answer to “why vitamin C (or anyother) is not working for this condition/disease?” question, please don’t “deconstruct” things. Have some serious anti-these study and prove them wrong. Nobody is doing that. And the story about how Vitamin C is miraculous or placebo is going on and on and on, and all you hear is phanatics from CAM and other side. I really don’t have the mildest trust in the pharmaceutical and drug industry because it gives the doctors full freedom to “make mistakes” which is what they call killing people. If you don’t believe that your body needs essential nutrients like vitamins and minerals to live and fight death and disease properly, and you do believe that antibiotics, statins, cytostatics and pain killers are necessary tools of “modern” medicine, think again. I don’t take body functions for granted, and I don’t think puting unnecessary drugs or food supplements into the body will make it live longer. But I would always feed the body so that it can fulfill it’s functions in times of trouble, and then put foreign drugs into it. How many doctor’s and “Scientists” are thinking the same way about that today, what do you think?
    I like your blog and read it regularly, and I like your introspective and critical view, but attacks just to judge results and not offer explanation are not far from blind faith of the awful “CAM”, just on the other side of the same thing. In other words, it is easy to shadow something, but hard to give light and make a step forward …

  5. #5 DonZilla
    August 14, 2008

    “I really don’t have the mildest trust in the pharmaceutical and drug industry because it gives the doctors full freedom to “make mistakes” which is what they call killing people.”

    And CAM practitioners (the sleazy ones) give the gullible full freedom to kill themselves (after separating them from their money, of course).

  6. #6 Paul
    August 14, 2008

    “If you don’t believe that your body needs essential nutrients like vitamins and minerals to live and fight death and disease properly, and you do believe that antibiotics, statins, cytostatics and pain killers are necessary tools of “modern” medicine, think again.”

    Nobody here, least of all Orac, is claiming that good nutrition isn’t important for cancer patients. I think we’ll all happily agree that it is vital. What he is doing is to challenge claims made about particular nutrients that go way beyond what the scientific and medical evidence justifies.

    In any case in the above post Orac made clear in his post Vitamin C was being used as a drug rather than a nutrient, all he’s doing is subjecting it to the came critical examination that he’d apply to any other anti-cancer drug candidate.

  7. #7 Dangerous Bacon
    August 14, 2008

    “… please, if you don’t know how to explain the exact mechanism and have a precise answer to “why vitamin C (or anyother) is not working for this condition/disease?” question, please don’t “deconstruct” things. Have some serious anti-these study and prove them wrong.”

    The way science works is that you propose a theory, figure out how to test it and submit evidence that you think validates the theory. Others will analyze your results and if they are sufficiently encouraging/positive, will attempt to replicate them and more firmly establish the finding.

    It is not the job of scientists to “prove them wrong”. It is “their” job to prove that they are right. Otherwise, no competent scientists would get anything done because they’d be constantly running around in search of enough money (and time) to disprove every wack-a-doodle theory in existence.

    There will probably be followup work on intravenous vitamin C. Until (and if) that is done to establish this therapy as valid for cancer, it is perfectly legitimate to analyze the results and put them in perspective.

    “But I would always feed the body so that it can fulfill it’s functions in times of trouble, and then put foreign drugs into it. How many doctor’s and “Scientists” are thinking the same way about that today, what do you think?”

    Lots of them. The role of good nutrition, calorie limitation and avoiding smoking and excess drinking are central to public health efforts.

    “I really don’t have the mildest trust in the pharmaceutical and drug industry…”

    I find that people who pride themselves on this lack of trust are also the quickest to fall for quackery, particularly if it is promoted by those who encourage outlandish suspicions about mainstream medicine and hype their product with the claim “They don’t want you to know”.

  8. #8 Kemist
    August 14, 2008

    …”if you don’t know how to explain the exact mechanism and have a precise answer to “why vitamin C (or anyother) is not working for this condition/disease?””

    hum, no sorry, that’s not how it works. If it worked that way, then we could ask something as absurd as :

    “Please explain the exact mechanism by which ice cream can’t shrink tumors”

    Do you find it ridiculous ? I hope so.

    The problem is that CAM modalities have been explored, and at most, have been found underwhelming. At very high costs of academic money, which has become rarer and rarer in both canada and US (hey, I know, my institute has been a victim of this). No matter how much is spent in those underwhelming studies, nobody in the CAM industry will stop claiming the same false things.

    I would like to see more CAM money spent on things that might actually work, such as natural compounds found in microorganisms or plants (which yielded stuff like taxol, a truly efficient mainline chemo drug), and less on bullshit. You should also want your tax dollars spent wisely, as it would allow you to receive efficient treatment at lower costs, rather than leaving useful research to pharmas.

  9. #9 DPSisler
    August 14, 2008

    Orac,

    Can you determine the amount of Vitamin C that this translates into if you squeezed and orange and obtained 4 oz. of juice? I believe the issue is that news reporters, and CAM practitioners hear “Vitamin C cures cancers” and believe that just going out and drinking Orange juice will solve all their issues (i.e., Posted by: iznogud | August 14, 2008 11:06 AM). From my non-scientific understanding of this article is that the doses are HUGE and have to be injected via IV. Thus, I would love to see the translation that states, “…this is equivalent of juicing 1,000 oranges twice a day and injecting it into your vein!” No one doubts the benefit of good nutrition. What is doubted is the benefit of high doses of Vitimin C versus other therapies. For the lay person, this type of analysis may be beneficial in understanding the context of the “proposed cure”.

  10. #10 Donna
    August 14, 2008

    Would so much Vitamin C have an effect on the pH of the body? Aren’t there claims that cancer thrives in acidic conditions? I know my sister (who has had cancer) is trying to balance her pH through her eating, but I understood that our bodies usually do a good job of balancing the pH no matter what we eat.

  11. #11 Ms. Clark
    August 14, 2008

    I wondered what Orac would say about this when I read about it in New Scientist.
    http://www.newscientist.com/channel/health/mg19926683.700-vitamin-c-cancer-patients-friend-or-foe.html
    “Levine explains that larger amounts of vitamin reach the tumour when it is injected compared with when it is taken orally. And while vitamin C usually acts as an antioxidant, in these large amounts it causes the formation of hydrogen peroxide – a powerful oxidising agent that kills cancer cells. He suggests that intravenous vitamin C could be a useful addition to conventional cancer therapy.


    Definitive answers will only come from subsequent larger trials. However, given recent reactions to a drug called DCA, which some patients began taking without medical supervision after reading about promising results on cancer cells, patients may take matters into their own hands. This could be dangerous. “I would not recommend that people inject themselves with vitamin C,” says Len Lichtenfeld of the American Cancer Society in Atlanta, Georgia.

    Nor should they take large doses of vitamin C in pill form, says David Agus, an oncologist at the Cedars-Sinai Medical Center in Los Angeles, California. Drisko and other supporters of complementary approaches suggest that antioxidant vitamins can aid cancer therapy and reduce side effects. Indeed, many cancer patients take antioxidant vitamins without telling their doctors. But conventional chemotherapy and radiotherapy are thought to work in part by generating free radicals which kill cancer cells. Because antioxidant vitamins can mop up these radicals, they may interfere with cancer therapy. “You want to make sure you’re not taking supplemental vitamins,” says Agus.

  12. #12 Peggy
    August 14, 2008

    DPSisler: According to Wikipedia, a 3.5 ounce (100g) orange contains 45mg of Vitamin C. The Phase I trial used 1.5 g/kg ascorbic acid, so for a 68kg (150 pound) adult, that would be a dose of 102g or 102,000mg. Divide that number by 45mg and you get 495 pounds of oranges (or 2,266) worth.

  13. #13 Dr. T
    August 14, 2008

    Once again, I remain puzzled as to why there is such intense interest in what, even if it “works,” strikes me as a cumbersome and only mildly effective therapy.

    My belief is that lazy pseudoscientists do this because vitamin C is easy to get and easy to work with, and it has an instant recognition factor in a journal article title. They also can use the weak ‘it’s an antioxidant’ argument to justify their research.

    As you know, there are far too many mediocre medical researchers competing for grants, publications, and tenure. If shoving ascorbic acid into rats can get a publication, then someone will do it while knowing there is almost no chance of successful treatments.

  14. #14 Dr. T
    August 14, 2008

    The study used incredibly high concentrations of ascorbic acid administered in hypertonic solutions. Did the mice experience significant hemolysis? (I don’t have access to the study to check.) Could the slowed tumor growth be due to relative hypoxia? Growing tumors use more oxygen than normal tissues and would be more affected by anemia. If so, then this entire study may actually show that anemia slows tumor growth. Hey, we could go back to leeches as a treatment!

  15. #15 NM
    August 14, 2008

    Dr T

    I alreay employ homeopathic leeches in all of my homeopathic patients who have homeopathic cancer. There have been zero fatalities so far. I hereby claim victory over big pharma, AMA illuminatii conspiracy. End of debate.

  16. #16 Kemist
    August 14, 2008

    “Aren’t there claims that cancer thrives in acidic conditions?”

    This is a bogus claim, confusing correlation with causation.

    Basically, solid tumors do not ‘thrive’ on acidic conditions, but rather incidentally cause their environment to become acidic. That is because they grow so fast they are not able to get rid of all their CO2 the normal way (transport in red blood cells, release in lungs). So they rely on dirty tricks, like dissolving CO2 by making H2CO3 (carbonic acid) using enzymes called carbonic anhydrases. The local increase in H2CO3 concentration around the tumor causes to pH to become acidic, which in turn makes certain chemotherapy agents, like carboplatin, to become less effective.

    Incidentally, the enzymes involved in this phenomenon are actively researched.

  17. #17 D. C. Sessions
    August 15, 2008

    What I can’t get over is: how?

    How, please someone tell me, do you get that monster dose of buffered ascorbate into someone without either ruining blood vessels or screwing their electrolytes out of recognition? Half a freaking kilogram? Eeep!

  18. #18 Orac
    August 15, 2008

    Actually, in the clinical trial, it only took between .7 and 1.5 g/kg of ascorbate to reach the same blood level as in mice. That’s only around 50 to 105 g. Much less. :-)

  19. #19 DPSisler
    August 15, 2008

    Peggy: Thanks! The equivalent of 2,666 oranges a day. I think that qualifies as “excessive”, no?

  20. #20 anthony serafini
    August 15, 2008

    I applaud the above article. The authors are quite right in saying that in these kinds of doses ascorbate is acting as a drug and that TONS of caution are needed before getting all excited as the Pauling puppets would have us do. Particularly telling is this quote from the above article:

    “look at the study itself. There’s one interesting thing that stands out right away when I look at it, and that’s that the manuscript was received for review on May 1 and accepted for publication on June 6. That’s incredibly fast, and it makes me think that this article was communicated, rather than submitted to peer review. (The manuscript lists the article as having been “edited” by Academy member Bruce Ames.) One thing that most people don’t understand about PNAS is that any member of the National Academy of Sciences can submit a manuscript and essentially choose its reviewers, whether that manuscript is by the member or “communicated” to the journal for another investigator. Indeed, getting a paper published in PNAS is quite easy for an Academy member and incredibly difficult for a non-member who does not have the connections that allow him to line up an Academy member willing to act as referee and thus is forced to submit his manuscript directly to the journal. On the other hand, PNAS used to be used more often that many would like to admit as a dumping ground by Academy members for their lesser work because of how easily they could publish in it. (Indeed, Linus Pauling first published his truly execrable retrospective and unrandomized “study” purporting to show that high dose vitamin C prolonged the lives of patients with advanced cancer in PNAS in the 1970s.”

    This is exactly right ANY NAS member can get this work (usually rejected by other journals already) into the PNAS.

    Sure, we should see what develops with this new injectable ascorbate thing, but I for one am not holding my breath. I’m putting my money on the important work carred in such things as Judah Folkman’s work on tumor angiogenesis factor Harvard, Steven Grant’s work at Virginia Commonwealth University on using multiple drugs to attack cancer, etc. For a detailed history of this whole controversy see my book LINUS PAULING: A MAN AND HIS SCIENCE, originally published by Paragon and Simon & Schuster and now published by iUNIVERSE.

  21. #21 Donna
    August 15, 2008

    Kemist: Thanks, the information about acidic conditions and tumors was very helpful.

  22. #22 khedges
    August 16, 2008

    My lab did some experiments to see if vitamin C could protect our animals (annelid worms, Lumbriculus variegatus) from copper toxicity, since the mechanism of copper neurotoxicity is presumed to involve generation of free radicals. Not only did vitamin C fail to protect the animals, it was toxic to them. (I belive we were bathing them in micromolar concentrations.) My PI has read pretty extensively about antioxidants, and has concluded that supplementation with antioxidants is generally not a good idea because they can also become pro-oxidants. Free radicals are just products of a reduction-oxidation reaction involving one spare electron, so if an antioxidant takes up spare electrons, it can release them, too.

    So I’m not surprised to see that high doses of vitamin C induce H2O2 production, but I am rather skeptical of claims that this only occurs in tumor cells. If the tumor has low levels of catalase, the enzyme that breaks down H2O2, it may accumulate more H2O2, but at those concentrations I don’t see how normal cells could defend themselves adequately for an appreciable length of time.

    I work with Caenorhabditis elegans, the famous nematode model organism, and other labs’ studies have shown whole-body toxicity of vitamin C in excess. I think the researchers were trying to use vitamin C to prevent the drug they were studying from oxidizing in contact with air, and their “no drug/ascorbate only” control showed a lot of sick worms. Unlike Lumbriculus, they’re tough little things with cuticles like hazmat suits. (Although I just learned that they express enzymes on the outside of the cuticle that create H2O2, perhaps as a defense against pathogenic bacteria. (C. elegans eats bacteria, but is also susceptible to attack by many types. It has innate immune defenses and can alter its behavior to avoid exposure. Chemical defenses wouldn’t be out of the question.)

  23. #23 Kemist
    August 16, 2008

    As a medicinal chemist, I’m also very weary of the anti-oxidant claims. Especially when applied to vitamins, whose primary effect is not ‘anti-oxidant’. There are so many classes of molecules, regardless of potency or selectivity, that are routinely designated as ‘anti-oxidant’, that it becomes difficult to take such claims seriously anymore.

  24. #24 Karl Schwartz
    August 17, 2008

    July 25, 2008. Annals of Oncology, doi:10.1093/annonc/mdn377

    Phase I clinical trial of i.v. ascorbic acid in advanced malignancy

    Conclusion: High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.

  25. #25 Orac
    August 17, 2008

    Yes, that’s the phase I trial I mentioned in my post.

  26. #26 Dr Aust
    August 17, 2008

    Completely tangential, but re. C. elegans eating bacteria: this is the basis of what I always though was one of the coolest scientific techniques ever, in which C. elegans genes can be silenced in the whole worm by simply letting the little guys “graze” on a lawn of E. Coli engineered to make the silencing RNA sequence.

    [doi:10.1016/S0378-1119(00)00579-5]

  27. #27 ella
    September 4, 2008

    Deficiency in vitamin c creates problem in later stages of life. Cancer patients also need to take proper care of themselves.

    ————-

    Ella

    Holistic Rehab

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