In the 1980s, Nobel laureate Linus Pauling, Ph.D., and researchers at the Mayo Clinic and Mayo Foundation in Rochester, Minn., clashed publicly over the merits of vitamin C in treating cancer. While Pauling maintained that terminal cancer patients who took vitamin C daily lived three to four times longer than patients who did not take vitamin C supplements, Mayo researchers in three studies concluded that vitamin C supplementation had no advantage over placebo therapy.
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In one camp are physicians like David Golde, M.D., physician-in-chief of Memorial Sloan-Kettering Cancer Center, New York, who believe that vitamin C supplementation could derail the beneficial effects of chemotherapy or even radiation. In the other camp are laboratory scientists such as Kedar N. Prasad, Ph.D., professor of radiology at the University of Colorado Health Sciences Center, Denver, who argue that high doses of antioxidants including vitamin C may not only protect normal cells during cancer treatment, but may actually help fight tumors. Complicating the situation is the lack of well-controlled clinical trials, coupled with the unknown applicability of laboratory findings to human cancer patients.
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Numerous laboratories have shown that human tumors contain high concentrations of ascorbic acid, commonly called vitamin C much higher concentrations than are found in noncancerous cells. Golde et al.'s study sought, and found, a mechanism that could explain how that higher concentration might be obtained. According to Golde's summation: "Tumors that cannot transport ascorbic acid can take up rather large quantities of vitamin C by oxidizing the ascorbic acid to dehydroascorbic acid and then transporting it in through the glucose transporters," Golde wrote. "And these tumor cells have a lot of glucose transporters, a characteristic of cancer."
Logic vs. Data
In their conclusion Golde and his research team found that "the increased intracellular concentration of vitamin C may have effects on tumor growth and the tumor's ability to respond to oxidative stress associated with chemotherapy and radiation therapy."
Vitamin C is not produced by the body but is an essential micronutrient. In addition to stimulation of the immune system and other functions, vitamin C acts as an antioxidant to protect tissues from cellular damage caused by free radicals. Oxidative mechanisms, however, are one way in which chemotherapy and radiation therapy inhibit the growth of cancerous cells. Hence, the reasoning: if many standard cancer treatments act by promoting oxidation, then consuming an antioxidant supplement such as vitamin C during standard cancer treatment is clearly counterproductive.
Prasad said that in the 1970s he would have agreed with this reasoning: "If I didn't know the literature, I would have said, Yes, antioxidants will protect against radiation damage because two-thirds of the damage produced by radiation is by free radicals. And you are telling me to use antioxidants to destroy free radicals, forget about it!' But the data today show the contrary."
In multiple laboratory experiments since 1980, Prasad and his colleagues at the University of Colorado have found that high doses of antioxidants such as vitamin C not only can protect normal cells during cancer treatment but also can help fight tumors. In this way, antioxidants may actually improve standard cancer therapy. Prasad explains that the vitamins are selective, inhibiting only the growth of cancer cells.
Why does this happen, in light of what is known about antioxidants and cancer treatments?
"I cannot say why they are selective," said Prasad. "My hypothesis for what is happening, which we are now testing, is that the normal cell has homeostatic control for the uptake of antioxidants like vitamins C and E. So, you can give high doses and normal cells acquire only what's necessary to function.
"The cancer cells, it looks like, have lost this mechanism of control of antioxidant uptake and therefore the antioxidant accumulates at a higher level. When it accumulates in cancer cells, the intracellular excess [of antioxidant] initiates a series of genetic events which ends up in cell death, growth inhibition, or differentiation."
As a result of his experiments and observations, Prasad feels that cancer treatment should include supplements of vitamin C, as well as vitamin E and beta-carotene. He does not favor the use of a single antioxidant alone, referring to studies suggesting that the use of single vitamins in cancer treatment are effective only at very high, potentially toxic doses. With multiple antioxidants, however, a lower dose of each vitamin can be used and, when taken in proportional amounts, the interaction of the different antioxidants would prevent the generation of free radicals. Prasad also emphasizes his belief that diet, lifestyle, and vitamin supplementation are three equally important components in cancer treatment.
The Fenton Reaction
Golde and numerous other clinicians disagree. They recommend that their patients, especially those who have diseases where vitamin C has actually been measured in the cells, such as chronic lymphocytic leukemia or breast cancer, refrain from antioxidant supplementation during cancer treatment.
The crux of this vitamin C debate is possible differences between in vitro and in vivo studies.
Golde said it is not surprising that laboratory scientists would see destruction of cancer cells following administration of vitamin C in vitro. He refers to a process known as the Fenton Reaction, in which metal ions, when combined with a reducing agent such as ascorbate, leads to a cycle that causes cellular damage.
"I'm not sure that the Fenton Reaction really occurs in the body because there's almost no free metal ion copper and iron are bound." Golde continued: "I think a lot of the confusion relates to the notion of the Fenton Reaction actually occurring in the body. . . . So I'm skeptical. I actually have some concerns about feeding the cancer cell."
Prasad responds that the Fenton Reaction would occur in the body. "There are free metal ions in plasma, in the brain, in all organs. And if vitamin C is there, it will interact with iron or copper or manganese." And he reiterated that adding vitamin E supplements to vitamin C would prevent the generation of free radicals. "It is an experimental fact, it is a clinical fact, that antioxidants at high doses are selective for inhibiting the growth of cancer cells," Prasad said.
It is the paucity of clinical data, however, that leads Golde and many other physicians to be cautious about the use of vitamin C supplements by cancer patients. Although Prasad cited numerous in vitro and animal studies, as well as support for their applicability to in vivo human conditions, large, well-designed clinical trials on the use of antioxidants during chemotherapy and radiation therapy are still lacking.
Kara M. Kelly, M.D., assistant professor of pediatrics in the Division of Oncology at Columbia University's College of Physicians and Surgeons, New York, summed up the status of the debate in Oncology (July 1999): "All of these studies had a limited number of patients," she wrote, "and survival data were based on comparisons with historical controls. Therefore, no conclusions about the benefits of supplementation can be drawn from these studies."
Wait and "C"
"I can't stress enough," said Linda Nebeling, Ph.D., R.D., acting chief of the Health Promotion Research Branch in the Division of Cancer Control and Population Sciences at the National Cancer Institute, "the importance of taking caution against grasping the conclusions of in vitro studies and promoting them to patients."
Prasad said that the Cancer Treatment Centers of America will initiate a large, double blind clinical trial next spring that will include a multivitamin protocol in combination with standard therapy. Until more such trials take place and report positive conclusions, many clinicians will follow Nebeling's advice and wait for clinical trials to definitively show the effect of vitamin C and other antioxidants on human cancer patients.
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