The multifunctional carotenoids: insights into their behavior.

Because it is widely held that damage to DNA by reactive species is a significant contributor to carcinogenesis, it has been postulated that antioxidants in supplements or in foods containing them, which decrease oxidative DNA damage, should have a protective effect against cancer. In antioxidant–cancer risk studies the most common oxidative biomarkers that have been used are: 8-hydroxyguanine in urine, the comet assay in leukocytes, various measures of ‘‘total’’ antioxidant capacity in blood, and serum levels of antioxidant nutrients. It has been shown in many studies that DNA strand breaks can be reduced by antioxidant supplements or by various combinations of fruits and vegetables that are high in antioxidant nutrient content. It is noteworthy, however, that in a study by Duthie et al., the combination of 100 mg of vitamin C, 280 mg of vitamin E, and 25 mg of b-carotene reduced DNA damage, as reflected by the comet assay, only in smokers but not in nonsmokers (1). Mixed results have also been seen when urinary 8-hydroxyguanine was used, and observed effects may not be long lasting. The question remains, therefore, do these biomarker assays of oxidative stress have any predictive value with regard to cancer incidence? The simple answer is that we don’t know. Even if we disregard the technical problems of lack of standardization of the assays in various published studies, no prospective epidemiologic or intervention studies have been done in human populations to show that individuals with lower levels of DNA strand breaks have a lower risk of cancer, or indeed that diets or antioxidant supplements can lower the number of DNA strand breaks over the long run (e.g., years). What is known is that antioxidants can alter short-term oxidation status however it is assayed, but we have no idea of the cancerlowering predictive value of these assays. In this article b-carotene will be used as a model antioxidant in an attempt to answer the question of the clinical significance of diet and changes in oxidative biomarkers with regard to cancer risk. It is now realized that different oxidative effects (antioxidant, pro-oxidant) of b-carotene can be seen, depending on its concentration and other conditions (e.g., the oxygen concentration) (2). Epidemiologic studies have shown an inverse relation between dietary or serum values of b-carotene and the incidence of lung cancer (3). Thus, it was against all expectations that b-carotene given in high doses to smokers resulted in an increased incidence of lung cancer in 2 intervention trials (ATBC, CARET) (4,5). The original interpretation of these trials was that dietary b-carotene in epidemiologic studies was simply acting as a surrogate for some other factor, or that case control studies (the design used in most of the epidemiologic studies on b-carotene) were inherently biased. However, another bothersome explanation was that b-carotene at high dose could be working to promote cancer. It was noted that in the 2 b-carotene intervention trials that resulted in a higher incidence of cancer, the serum b-carotene levels achieved were significantly higher than that in another intervention trial in which there was no increase in lung cancer in response to supplementary b-carotene (Physicians Health Trial) (4–6). These disparate findings could be accounted for by the different concentrations of b-carotene reached in tissue. Although the b-carotene intervention trial results were shocking at the time, other studies have also shown that supplementary antioxidants can increase the incidence of cancer. For example, it has been reported that vitamin E supplementation in patients with treated head and neck cancers resulted in an increased occurrence of secondary primary cancers during the supplementation period (7). This study included 522 patients with stage 1 head and neck cancers who were treated by radiation. These patients were supplemented with 400 international units of vitamin E and 30 mg of b-carotene or placebo, which began on the first day after radiation therapy, and these treatments were continued for 3 years. During the course of the trial, b-carotene was discontinued after 156 patients had been enrolled in the study. The remaining patients received only vitamin E. After a median follow-up of 52 mo, second primary cancers and recurrences of the first tumorwere counted. It was found that patients receiving the vitamin E supplements had a higher rate of second primary cancers during the supplementation 1 Published in a supplement to The Journal of Nutrition. Presented as part of the conference ‘‘The Use and Misuse of Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation’’ held July 12–13, 2005 in Bethesda, MD. This conference was sponsored by the Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA), Department of Health and Human Services (DHHS); the Office of Dietary Supplements (ODS), National Institutes of Health, DHHS; and the Division of Cancer Prevention (DCP), National Cancer Institute, National Institutes of Health, DHHS. Guest Editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; and Claudine Kavanaugh, CFSAN, FDA. Guest editor disclosure: H.E. Seifried, no relationships to disclose; C. Kavanaugh, no relationships to disclose. 2 Author disclosure: no relationships to disclose. * To whom correspondence should be addressed. E-mail: rob.russell@tufts.edu.