Vitamin C and cancer revisited

Sometimes I have to look for blog ideas, trolling through various alternative medicine sites, medical news sites, or science news feeds or my medical and science journals. Sometimes ideas fall on me seemingly out of the blue. This is one of the latter situations. This time around, as I do twice a month 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.

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. That was more than two years after my last magnum opus about this topic. But this latest study examined an aspect of the vitamin C phenomenon that I hadn't considered before. In fact, it found results that I had not seen reported before.

Given that, how could I resist throwing myself 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. Otherwise, silence.

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. These are all specialty publications, for the most part. To find out why we've heard so little about this study, 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

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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, as this graph shows:

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. But, then, why do I ever expect anything different?

REFERENCE:

M. L. Heaney, J. R. Gardner, N. Karasavvas, D. W. Golde, D. A. Scheinberg, E. A. Smith, O. A. O'Connor (2008). Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs Cancer Research, 68 (19), 8031-8038 DOI: 10.1158/0008-5472.CAN-08-1490