Vitamin C strikes (out) again

I didn’t think I’d be revisiting this topic again so soon. After all, I wrote one of my characteristic magnum opuses (opi?) less than two months ago, when I asked whether a recent animal study had vindicated Linus Pauling’s belief that high dose vitamin C is a highly effective cancer treatment. After that tsunami of verbiage that can only be exceeded by my fellow blogger Dr. Atwood when he’s on a roll doing a multipart deconstruction of some woo or other, I thought it would be best to give it a rest for a while. I guess less than two months will have to be enough.

The reason struck me as I was perusing the very latest issue of Cancer Research, hot off the presses October 1. As I did so, it didn’t take me long to come across an article from the Memorial-Sloan Kettering Cancer Center and the Herbert Irving Comprehensive Cancer Center at Columbia entitled Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs, whose first author is Dr. Mark Heaney.

Once more into the fray!

You may recall that, when last I discussed the topic of vitamin C as a “cancer cure,” I discussed a recent study out of Mark Levine’s laboratory at the Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, at the National Institutes of Health. At the time, Dr. Levine argued that the doses of vitamin C used in previous randomized, double-blind trials of vitamin C against cancer were oral and thus did not produce levels of ascorbate in the serum high enough to kill cancer cells because absorption of vitamin C is limited by the rate that the gastrointestinal tract can take it up. He argued that, to reach the very high doses found to be necessary in cell culture to kill lymphoma cells preferentially to normal cells,. We’re talking huge concentrations ranging from 2 to 20 mM, which are levels of active drug that are virtually unheard of for normal drugs. In mice, he showed that attaining such high blood concentrations was feasible in mice and that they demonstrated a mild antitumor effect in a three mouse models of cancer and differential toxicity to cancer cells over normal cells through, paradoxically, the induction of reactive oxidant species, as it turns out that this particular antioxidant can become a pro-oxidant at sufficiently high concentrations. Overall, I concluded that the available evidence suggests that, even if vitamin C does have an anti-tumor effect, it’s likely to be modest, making it a long run for a short slide; in other words, huge doses of vitamin C, such that they are difficult to get into the patient, for a pretty wimpy benefit.

Of course, as I pointed out before, every time there’s a study suggesting that “vitamin C might work after all,” the press go ga-ga all over it. Certainly that’s what happened for Dr. Levine’s cell culture study back in 2006 and his animal model study a couple of months ago. So, take a guess. What do you think the reaction to to the study I mentioned above published in the October 1 issue of Cancer Research?

Crickets chirping.

Yes, the silence was deafening. I wonder why? True, I did find articles in the Canadian press, in Medpage Today, and Medscape, but not much anywhere else. To find out why, let’s look at what the study found:

October 2, 2008 — Large supplemental doses of vitamin C could interfere with the therapeutic cytotoxic effects of a wide range of chemotherapy agents, suggests a new preclinical study. Although the finding comes from research conducted in cancer cell lines and mice, the authors say the conditions they created are similar to those found in the body, and speculate that the same mechanism might affect patient outcomes.

“It is possible that vitamin C supplementation may alter the effectiveness of commonly used chemotherapeutic agents and adversely influence treatment outcome,” the researchers write in the October 1 issue of Cancer Research


So what did the researchers do? First, you have to understand that a common mechanism of action of many chemotherapeutic drugs is the generation of reactive oxygen species (some of which are known as oxygen free radicals), which the result in DNA damage. Consequently, one might reasonably hypothesize that vitamin C (ascorbate) might interfere with the action of some of these chemotherapeutic agents. On the other hand, if Dr. Levine is correct it could be argued that ascorbate might potentiate the activity of such chemotherapeutic agents.

Therefore, first, as scientists so often do, investigators tested combinations of different chemotherapeutic agents with increasing concentrations of vitamin C. One difference between this study and the previous two studies by Dr. Levine is that the range of ascorbate concentrations examined was from 0 to 0.5 mM, which is 10 to 20 times lower than the concentrations that Levine used. In any case, what he found was that treating two different leukemia and lymphoma cell lines with ascorbate at those concentrations before treating them with chemotherapeutic agents, including mechanistically dissimilar agents such as doxorubicin, which intercalates with DNA and causes DNA breaks; methotrexate, which inhibits folate metabolism; cisplatin, which crosslinks DNA; vincristine, which interferes with microtubule function; and imatinib mesylate (better known by its trade name of Gleevec), a selective inhibitor of the activity of a protein called bcr-abl, which is the oncogene that plays a central role in the development of chronic myelogenous leukemia (CML). The point is that these drugs all have very different mechanisms of action, and the finding was that vitamin C inhibited their effects. At the concentrations used, it didn’t inhibit or stimulate the growth of cells in and of itself. However, it did interfere with the actions of these drugs, decreasing their cytotoxicity to tumor cells by 30-70%.Next, they tested the effect of vitamin C and chemotherapy in mouse models of cancer using 250 mg/kg, again a much lower dose than what Dr. Levine used. Once again, vitamin C interfered with chemotherapy.

What was puzzling about these results is that not all of these drugs are thought to have as part of their mechanism of toxicity the generation of reaction oxygen species, and yet vitamin C interfered with them all. The question then became: Why? A series of additional experiments showed that it wasn’t because vitamin C made tumor cells better able to pump chemotherapeutic agents out. They then compared vitamin C to another chemical (N-acetylcysteine), which like vitamin C helps cells replenish their supply of free radical scavenging thiols such as glutathione, which neutralize reactive oxygen species. When cells were treated with N-acetylcysteine, it only protected them from one of the five chemotherapeutic agents, cisplatin, and vitamin C had minimal effects on intracellular reactive oxygen species. This result suggested that vitamin C works through a more general mechanism than simply an antioxidant mechanism. A further experiment showed that vitamin C was protective against mitochondrial damage caused by chemotherapeutic agents, a mechanism of action common to all five of the drugs. Dr. Heany speculates:

“Our study is a preclinical model that addresses only the situation when vitamin C is given in the setting of chemotherapy treatment,” Dr. Heaney emphasized. There have been no clinical studies of this topic so far, he said.

However, the finding could be of potential concern because “many people, cancer patients included, take supplemental vitamin C,” Dr. Heaney pointed out. Clinical studies of vitamin C supplementation in patients with advanced cancers have had mixed results. There are conflicting hypotheses, he explained. One theory is that vitamin C supplementation protects the cancer and is therefore detrimental to the patient. But there is also the opposite view, that vitamin C supplementation enhances the immune system or prevents indolent cancers from mutating more and becoming aggressive, which would be beneficial for the patient.

Asked to comment on this study, Len Lichtenfeld, MACP, deputy chief medical officer at the American Cancer Society said: “Vitamin C has a long history in cancer prevention and treatment. Although there is no evidence to demonstrate that vitamin C improves the outlook for patients with cancer, there are still reported observations that cancer patients continue to believe in the potential benefits of vitamin C. Although oncologists do not routinely recommend that patients with cancer take excessive doses of vitamin C, there are reports that cancer patients are being treated with vitamin C by alternative practitioners.”

Once again, it must be emphasized that this is a study in cell culture and a mouse model (in fact, much like the studies of Dr. Levine). It’s applicability to humans is not clear and requires testing. However, it does bring up an issue. Clinical trials are moving forward, spearheaded by Dr. Levine, of high dose intravenous vitamin C and cancer. Granted, the doses he is using are many times higher than what was used in the study showing vitamin C interference with chemotherapy. Also granted, Dr. Levine’s study implicates reactive oxygen species generated by vitamin C when it is present in very high concentrations, while Dr. Heaney’s study examined concentration ranges that are achievable with oral dosing. It’s not clear if the same results will apply. So what to do?

Dr. Heaney is cautious:

Lead author Mark Heaney, MD, PhD, from Memorial Sloan-Kettering Cancer Center, in New York, New York, told Medscape Oncology that he advises his cancer patients to avoid supplemental vitamin C during chemotherapy. “I recommend that my patients continue to eat a well-balanced diet that includes fruits and vegetables that contain vitamin C.”

“Such a diet could be expected to have moderate amounts of vitamin C as well as other important nutrients. There are no data to suggest that vitamin C obtained from fruits and vegetables is intrinsically different from vitamin C supplements. Given that our research was done in experimental model systems and was not a clinical trial, I am reluctant to predict a dose of supplemental vitamin C that could be extrapolated to our work. That said, oral vitamin C supplementation with doses as low as 250 mg over a 1-month period resulted in intracellular vitamin C concentrations in normal white blood cells that were close to those that we studied in white blood cell cancers,” Dr. Heaney said.

One thing that concerns me about this study is that any clinical trial that will be carried out with vitamin C and cancer will be chemotherapy plus vitamin C, not just vitamin C alone. After all, that’s the standard methodology for testing a putative chemotherapeutic agent: Add the experimental agent to standard of care chemotherapy. Based on Dr. Heaney’s result, a compelling case can be made that such a trial would be unethical, at least at the lower “megadoses” of vitamin C, because there is a plausible mechanism by which vitamin C might actually interfere with chemotherapy and thus do harm. At the the super high doses of vitamin C, such as the ones that Dr. Levine studied, we don’t know whether the vitamin C would interfere with chemotherapy based on a mechanism similar to that postulated in Dr. Heaney’s study or whether it might potentiate the activity of chemotherapy by generating reactive oxygen species, as the results of Dr. Levine’s studies might predict. However, I would argue that any study of super high dose vitamin C a la Dr. Levine plus chemotherapy would also be unethical, unless animal and cell culture data could be produced that would show that vitamin C as such high concentrations does not interfere with chemotherapy.

Another thing that bugs me about this study is that it’s another example of how the media reports anything having to do with Linus Pauling’s idea that megadoses of vitamin C can treat cancer. Whenever a study is reported that seems to be consistent with a use for vitamin C in treating cancer, almost inevitably it gets wide coverage. When a study is reported that suggests that high dose vitamin C has no use or–even worse–may be harmful, you hear nothing about it.

Same as it ever was.

Posted in: Basic Science, Cancer, Herbs & Supplements, Nutrition

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8 thoughts on “Vitamin C strikes (out) again

  1. bguilliams says:

    The plural of opus is opera. ;)

  2. thecardiffgiant says:

    magnum opus is neuter singular, and usually there’s only one, but I guess if you were amaz!ng enough you could write several magna opera (neuter plural). The problem, of course is that it’s easily confused with magna opera (feminine singular) which means ‘great effort’ or even ‘quite a day’s work’. Silly Latin.

  3. dopey says:

    From my brief look at abstracts published (via pubmed), there are many articles and of course no definitive answers, as is usually the case with any scientific pursuit. One simple positive (pro C, if you will) example: J Transl Med. 2008 Sep 12;6(1):50. The title is “Anti-angiogenic effect of high doses of ascorbic acid”. Although, not that a title or for that matter abstract is truly telling of the science, only a critical review of the results and assumptions, would do it for me.
    Commentary on Levine’s 2008 PNAS paper – (not sure if that is free access or not). from the commentary “metastases were present in ≈30% of athymic mice grafted with glioblastoma tumors, whereas no metastases were detected in similar mice injected i.p. with ascorbate. This observation warrants further investigation because metastases account for a substantial percentage of cancer mortality. ” Now again, I’m not in the vitamin C cures all diseases boat, I don’t know and haven’t educated myself enough to formulate an opinion, but reading statements like that makes me think that the title “vitamin C strikes out again” is a little strong. And seeing both sides of the argument being pushed (along with my ignorance), forces me to the center. And I’d have to say that perhaps the jury is still out.

    But the clinical trials sound interesting to me at least, as even if we don’t know the mechanism, the outcome will be interesting to see. Unethical? I don’t know. Maybe these patients are terminal anyway (haven’t looked at the trial myself). I always like to note, that there are many drugs used in the clinic that we don’t know how they work, just that they work. So in my mind, clinical trials always have potential in that respect. Again, not that I am a firm believer one way or the other on this particular issue.

    As for the comment about the media picking this up, what does the media care about vitamin C potentially not working… not an exciting story. IMO, the media is sensationalist. E.g., a cure for cancer that you can buy at walmart! now that’s exciting.

  4. Actually, the reason I put the “out” in parentheses was to weaken it a bit.

    In any case, I discussed Levine’s studies in gory detail here:

    The entire point is that vitamin C against cancer is a long run for a short slide. The best data out there suggest that, at the very best and most optimistic, the effect of vitamin C on cancer is modest and requires incredibly, ridiculously high doses to achieve. If you tell a pharmacologist or phase I researcher that you have a drug but it requires a concentration of 10 mM to have a relatively modest effect, he or she’d almost certainly tell you thanks but no thanks. Drugs requiring such huge doses are difficult to administer and if they aren’t significantly better than what we have there’s little reason to be very interested in them.

    Add to that a study that suggests that at lower doses the drug might actually interfere with chemotherapy, and you have a problem. Any other drug would probably be rejected as far as being particularly useful given this data. Not vitamin C. It appears immune to the usual mundane considerations usually applied to testing other drugs.

  5. oderb says:

    I’m neither a scientist or a physician and as such I’d be interested in hearing what people think of the argument below regarding this study.

Orthomolecular Medicine News Service, October 7, 2008
    Chemotherapy Doesn’t Work, So Blame Vitamin C
    (OMNS, October 7, 2008) When Memorial Sloan-Kettering Cancer Center announces that vitamin C may interfere with chemotherapy, the news media trumpet it far and wide. But before cancer patients throw away their vitamin C supplements, they need to know rest of the story.
    Most of the media dutifully reported the researchers’ claim that the equivalent of 2,000 mg of vitamin C “blunted the effectiveness of the chemotherapy drugs.” But only some of the media included a study author’s incredible statement that “If you take an oral dose even as low as 100 milligrams a day” even “that could be harmful” during chemotherapy (1)
    100 mg “could be harmful”? That’s the amount of vitamin C in a few glasses of orange juice. Something is very wrong here.
    First of all, this research involved mice with implanted cancerous tumors; it was not a trial on cancer patients. A mouse study is a long way from a human clinical trial. This obvious difference was conceded by the study authors. However, there is a more subtle, and probably much more important factor they did not consider: all mice make their own vitamin C. Indeed, mice make quite a lot. Adjusted for body weight, mice synthesize the human body weight equivalent of approximately 10,000 milligrams of vitamin C each day. (2) Incredibly, sick mice make even more. Mice given transplanted tumors become sick mice.
    Secondly, previous research has demonstrated that mice with cancer respond well to high-dose vitamin C therapy. One study found, “With an increase in the amount of ascorbic acid there is a highly significant decrease in the first-order rate constant for appearance of the first spontaneous mammary tumor. . . Striking differences were observed between the 0.076% ascorbic acid and the control groups, which synthesize the vitamin.” (3) Another study concluded that: “A pronounced effect of vitamin C in decreasing the incidence and delaying the onset of malignant lesions was observed with high statistical significance. By 20 weeks, approximately five times as many mice had developed serious lesions in the zero-ascorbate as in the high-ascorbate group.” (4) Interestingly enough, when this research was first publicized, the media discounted these findings saying that mouse studies were not particularly applicable to people.
    Thirdly, a mouse’s ability to make vitamin C, and a great deal of it, is an overlooked confounding factor that may well render the entire experiment invalid. If the Sloan-Kettering team had tried their experiment on Guinea pigs, their results might have been very different. Guinea pigs are more like human beings in that they cannot make their own vitamin C. As controls for comparison, the researchers also treated “no-added-vitamin C” mouse cancers with chemotherapy. Chemo worked just fine on those mice, by the researchers own admission. And each of those mice was internally synthesizing a body weight equivalent of 10,000 mg/day of vitamin C, even though given none supplementally.
    So how come 10,000 mg of vitamin C does not interfere with chemo treatment, and 2,000 mg – or even 100 mg – supposedly does?
    A sweeping recommendation warning cancer patients to not take supplemental vitamin C, not even 100 mg, is irresponsible. It is impossible to justify caution about taking 100 mg of vitamin C daily when your animal subjects made the equivalent of one hundred times that amount, and chemotherapy in them was still reported as effective. You cannot have it both ways. If a synthesized 10,000 mg of C does not interfere, there can be no real “interference” or “blunting” from a supplemental 2,000 mg. And most certainly not from 100 mg.
    The study did report tumor shrinkage, in both groups of mice receiving chemo. That is not surprising. Chemotherapy’s claimed success is based on tumor shrinkage. But tumor shrinkage, encouraging though it is, is not a reliable indicator of long-term cancer survival. As cancer research critic Philip Day puts it, many patients are “cured but dead” after five years, hardly a long-term survival. Day, noting that this is not because oncologists are not trying, explains the chemotherapy quandary: “You can be insincere, or you can be sincerely wrong.” (5)
    The Sloan-Kettering study team seems to have missed the essential point that vitamin C is not just an antioxidant. Inside cancer tumors, it also acts as a prooxidant, killing malignant cells. Comments Dr. Steve Hickey, of Manchester, UK: “Essentially, the paper seems to be rather misguided and shows a lack of understanding of the dual nature of vitamin C in tumors. Chemotherapy has been shown by over 40 years of clinical trials not to work in the majority of tumors, and its use is counterproductive.”
    Chemotherapy drugs have come and gone; the five year survival rate for cancer treated with chemo has remained virtually unchanged for decades. Unfortunately, just over 2% of all cancers respond to chemotherapy. Specifically, one scientific review concluded, “The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA . . . chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.” (6)
    Perhaps this new, very well-publicized study results from an ever-growing realization that chemotherapy is largely ineffective, and the search is on for the reason why. Vitamin C should not be made the scapegoat.
    Vitamin C, in doses well over 100 mg/day, is known to help prevent cancer. (7) Nearly 30 years ago, a review concluded that “Many factors involved in host resistance to neoplasia are significantly dependent upon the availability of ascorbate.” (8) Beginning in the 1970s, many well-designed studies show that very large doses of vitamin C improve both quality and length of life for cancer patients since they invariably are “significantly depleted of ascorbic acid.” When given intravenous vitamin C, “The mean survival time is more than 4.2 times as great for the ascorbate subjects . . . This simple and safe form of medication is of definite value in the treatment of patients with advanced cancer.” (9) Additional clinical trials have confirmed this over the past several decades. (10)
    Even more importantly, recent research indicates that in high doses, vitamin C is selectively toxic to cancer cells. That means vitamin C can function very much like chemotherapy is supposed to, but without the severe side effects of chemotherapy. “A regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian, pancreatic, and glioblastoma tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously.” (11)
    “Cautioning” the public to avoid taking any supplemental amount of vitamin C will decrease host resistance to cancer, increase the incidence of this dreaded disease, and shorten survival times. A cynic might say it will also create a larger market for chemotherapy.
    Is vitamin C a commercial competitor for chemo? To answer this, one needs to consider what appears to be serious conflict of interest at Sloan-Kettering. Bristol-Myers-Squibb makes chemotherapeutic drugs. According to a DEF 14A SEC filing of March 22, 2006, the Chairman of the Board of Bristol-Myers-Squibb is also a director of the Coca-Cola Company, and Honorary Chairman of Memorial Sloan-Kettering Cancer Center. ( A previous Bristol-Myers-Squibb Chairman of the Board was a director of the New York Times Company. He was also Vice Chairman of the Board of Overseers and the Board of Managers of Memorial Sloan-Kettering Cancer Center and Chairman of the Board of Managers of Sloan-Kettering Institute for Cancer Research. ( Some sources say that there are even more Bristol-Myers-Squibb directors who have or held positions on the board at Memorial Sloan-Kettering Cancer Center. (12)
    Positive endorsements for vitamin C as a cancer fighter are not in the interests of any pharmaceutical company. Scaring the public away from vitamin C might be profitable. It appears that Sloan-Kettering is biased. So are media reports that attack vitamins.
    If the Sloan-Kettering study authors’ recommendations to not take 2,000 mg, or even 100 mg, of vitamin C are followed, there will definitely be an increase in the number of people that need chemotherapy.
    (1) Doheny K. Vitamin C and chemotherapy: bad combo? Supplementing with vitamin C may reduce effectiveness of chemotherapy drugs, study shows. WebMD Health News. 

(2) Chatterjee IB, Majumder AK, Nandi BK, Subramanian N. Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci. 1975 Sep 30;258:24-47. 

(3) Pauling L, Nixon JC, Stitt F et al. Effect of dietary ascorbic acid on the incidence of spontaneous mammary tumors in RIII mice. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5185-9. 

(4) Pauling L. Effect of ascorbic acid on incidence of spontaneous mammary tumors and UV-light-induced skin tumors in mice. Am J Clin Nutr. 1991 Dec;54(6 Suppl):1252S-1255S. Read the full paper free of charge at 

(5) Day P. in the documentary film Food Matters, See also: Day P. Cancer: why we’re still dying to know the truth. Credence Publications, 1999. ISBN-10: 0953501248; SBN-13: 978-0953501243 

(6) Morgan G, Ward R, Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol (R Coll Radiol). 2004 Dec;16(8):549-60. 

(7) Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992 May;3(3):194-202. 

(8) Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. 1979 Mar;39(3):663-81. 

(9) Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3685-9. Read the original paper at 

(10) Murata A, Morishige F, and Yamaguchi H. Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. International Journal of Vitamin and Nutrition Research Suppl., 23, 1982. p. 103-113. And: Null G, Robins H, Tanenbaum, M, and Jennings P. Vitamin C and the treatment of cancer: abstracts and commentary from the scientific literature. The Townsend Letter for Doctors and Patients, 1997. April/May. And: Vitamin C and cancer revisited. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11037-8. Also: Riordan HD, Riordan NH, Jackson JA et al. Intravenous vitamin C as a chemotherapy agent: a report on clinical cases. Puerto Rico Health Sciences J, June 2004, 23(2): 115-118. 

(11) Chen Q, Espey MG, Sun AY et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11105-9. See also: Chen Q, Espey MG, Sun AY et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8749-54. And: Chen Q, Espey MG, Krishna MC et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9. And: Padayatty et al. Intravenously administered vitamin C as cancer therapy: three cases. Canadian Medical Association Journal, 2006. 174(7), March 28, p 937-942. Also: Riordan NH et al. Intravenous ascorbate as a tumor cytotoxic chemotherapeutic agent. Medical Hypotheses, 1995. 44(3). p 207-213, March. 

(12) Moss R. Questioning Chemotherapy. Equinox Press, 1995. ISBN-10: 188102525X; ISBN-13: 978-1881025252. See also: The Cancer Industry. Equinox Press, 1996. ISBN-10: 1881025098; ISBN-13: 978-1881025092.
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