Dietary antioxidant supplementation may boost melanoma risk in women

Key Points

Bordeaux, France - A new study suggests that dietary antioxidant supplementation does not help prevent skin cancer. In fact, in women, antioxidant supplements taken for a very long period may facilitate the development of skin cancer, especially melanoma.

"The SUVIMAX study is the first randomized cohort study evaluating supplementation with a combination of antioxidants at nutritional doses in the adult general population (in France)," says Khaled Ezzedine, M.D., Ph.D., associate professor of dermatology, department of dermatology, Hôpital Saint-André, CHU de Bordeaux, France, and the study's lead author. "The findings of the study indicate that there may be an independent link between antioxidant supplementation and skin cancer occurrence in women after controlling for conventional risk factors for skin cancer, notably skin phototype, sun exposure and history of sunburn."

Published online July 5 in the European Journal of Cancer, the study is the Supplementation in Vitamins and Mineral Antioxidants (SUVIMAX) study, a randomized, double-blinded, placebo-controlled, primary prevention trial testing the efficacy of nutritional doses of antioxidants in reducing the incidence of cancer and ischemic heart disease in the general population. The French adults in the study (7,713 women age 35 to 60 and 5,028 men age 45 to 60) received daily a placebo or a combination of ascorbic acid (120 mg), vitamin E (30 mg), beta-carotene (6 mg), selenium (100 lg) and zinc (20 mg) from 1994 to September 2002.

In the 1990s, experimental data and observational studies supported a beneficial protective effect of these particular antioxidants against cancer in general and skin cancer in particular, according to Dr. Ezzedine.

"Moreover, the combination of nutritional doses of antioxidants used in the trial was supposed to reproduce the content of fruits and vegetables contributing to a healthy diet," he says.

The research, including a study published in 2007 in the Journal of Nutrition, told a different story. In the first study, looking at the same database to determine whether supplementation with a combination of antioxidant vitamins and minerals could reduce the risk of skin cancers, the authors found no significant differences in skin cancer incidence among men in both groups. However, they reported that in women, there were 30 total skin cancers in the placebo group versus 51 in the antioxidant group. The incidence of melanoma among the female subjects was 4.3 times higher in the antioxidant group.

The post-intervention study in the European Cancer Journal, which followed the same subjects for five years after stopping antioxidant supplementation, showed that this harmful effect disappeared when supplementation was stopped. This suggests that it is not a spurious observation, according to Dr. Ezzedine.

Gender difference

It was striking, Dr. Ezzedine says, that the women in the SUVIMAX trial, unlike the men, had adequate dietary intake of antioxidants at the onset of the trial.

"So, besides hormonal factors, one hypothesis is that in this subgroup, supplementation was associated with harmful effects by overprotecting against apoptosis. This overprotection may be a mechanistic factor for the promotion or progression of cancer development, or both," he says.

Dr. Ezzedine says the discrepancy between these results and previous experimental data in animals may be explained by differences in the timing of the interventions. In animal models of cutaneous carcinogenesis, diet was enriched in antioxidants prior to irradiation with UVA or UVB, leading to a predominantly beneficial effect of treatment on DNA protection.

In contrast, in the SUVIMAX trial and related primary prevention studies, antioxidants were given only after many years of exposure to sunlight or other risk factors.

"At this stage, it may be too late for antioxidants to prevent DNA damage, whereas increased antioxidant exposure might exert a negative influence on antitumoral immunity, angiogenesis or apoptosis," he says. "This detrimental effect late in the disease process might explain why we observed a more pronounced effect upon melanoma, which requires a longer time frame over which to develop compared to other skin cancer types, and is presumed to be mainly induced by exposure to solar radiation during infancy."

In the specific analysis of skin cancer in the SUVIMAX trial, there was a significant relationship between serum levels of certain antioxidants provided by the supplementation and the occurrence of skin cancer in women. Hence, women with high antioxidant serum levels at the beginning of the study were more prone to develop skin cancer, Dr. Ezzedine says.