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 vitaminÂ 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 vitaminÂ 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, 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 vitaminÂ 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 vitaminÂ C," Dr. Heaney pointed out. Clinical studies of vitaminÂ C supplementation in patients with advanced cancers have had mixed results. There are conflicting hypotheses, he explained. One theory is that vitaminÂ C supplementation protects the cancer and is therefore detrimental to the patient. But there is also the opposite view, that vitaminÂ 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: "VitaminÂ C has a long history in cancer prevention and treatment. Although there is no evidence to demonstrate that vitaminÂ C improves the outlook for patients with cancer, there are still reported observations that cancer patients continue to believe in the potential benefits of vitaminÂ C. Although oncologists do not routinely recommend that patients with cancer take excessive doses of vitaminÂ C, there are reports that cancer patients are being treated with vitaminÂ 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 vitaminÂ C during chemotherapy. "I recommend that my patients continue to eat a well-balanced diet that includes fruits and vegetables that contain vitaminÂ C."
"Such a diet could be expected to have moderate amounts of vitaminÂ C as well as other important nutrients. There are no data to suggest that vitaminÂ C obtained from fruits and vegetables is intrinsically different from vitaminÂ 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 vitaminÂ C that could be extrapolated to our work. That said, oral vitaminÂ C supplementation with doses as low as 250Â mg over a 1-month period resulted in intracellular vitaminÂ 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?
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
"Yes, the silence was deafening."
Actually, the BBC reported on this.
I should add though that I agree that the coverage was not balanced enough.
Actually, I read about it in my local paper last week! It was the Ottawa Citizen.
Here's the online copy of that story from a sister paper the Montreal Gazette.
Thanks for your posting, it was most useful.
You typically say little about mouse models. I find that they rarely translate long-term into useable data on humans. Do you find otherwise?
I've copied the relevent part of Orac's post:
"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."
What a waste of time and effort. If Linus Pauling hadn't become senile immediately after winning a Nobel Prize, no one would be looking at vitamin C to cure cancer, colds, or cavities. Folate, vitamin E, and zinc are also antioxidants, but investigators aren't rushing out to prove they can cure cancer (though they did look at zinc and colds). The continued appeal of vitamin C is mystifying.
The continuing supersitious, hell, near-mythological view of Vitamin C as a "cure-all" may be in part due to the fact that it has been observed for centuries that diets that lack sufficient Vitamin C will cause Scurvy. To the untrained eye, "You will die if you don't get X" translates into "more and more X makes you healthier."
We should probably consider it a minor miracle that people aren't ignorant enough to apply that to water as well...
Dt. T said: "The continued appeal of vitamin C is mystifying."
Nah. Remember, vitamin C is virtually ubiquitous. You have copious amounts in citrus, broccoli, and lots of other foods. When the anti-science haters of evidence based medicine wanted a bogeyman to prove that BigBadPharma is suppressing a cure for cancer, they used Vitamin C, since it is so readily available. If it weren't, BigBadPharma would not appear to be so horribly evil.
fwiw - the plural of opus ("work") is opera in Latin, though opuses is perfectly acceptable (if less erudite sounding) as the English plural.
Just thinking of something here. Cancer drugs are sometimes used for other conditions. If this indicates that Vitamin C can interfere with Methotrexate for cancer treatment, how does it affect the use of MTX for other purposes, such as treating Rheumatoid Arthritis? Or is the dose of C too high to be relevant in most cases?
Ironically the plot you posted seems to indicate that vitamin C alone does have an effect over control. I wonder why the data for vit C stops before 20d? Does that mean all the mice died?
Anyhow - I would argue that without knowing how well vit C protects normal cells against chemo, it is inappropriate to claim that vit C is necessarily a bad combo with chemo. If vit C does have a protective effect on all cells, maybe combining vit C with chemo would allow for greater doses of chemo thereby regaining it's efficacy while reducing the side-effects.
And, in fact, there is at least one study, whose results ARGUABLY support the claim that intravenous C (IV-C) reduces the side effects of chemo.
There they tested IV-C in combination with 2 other chemo drugs for resistant multiple myeloma. Basically, they found that patients had fewer side effects from this treatment than from each drug alone.
Though, I will immediately concede the point that improved tolerance may be due to differing treatment schedules, and other factors. Regardless, the sad fact is that their study showed less of an effect for the combo that included vit C than for each drug alone.
27% effect for the combo and ~33% effect for each of the drugs.
And an even sadder fact can be found here:
Presumably phase I study for tolerance of IV-C reached a stage where some results could be published and although as expected IV-C was not found to be particularly toxic, unfortunately "No patient had an objective anticancer response."