Affiliation of author: Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Correspondence to: Peter Greenwald, M.D., Dr.P.H., Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Boulevard, Suite 2040, Bethesda, MD 20892-7309 (e-mail: greenwap{at}dcpc31.nci.nih.gov).
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INTRODUCTION |
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Summary of the ATBC Study and CARET |
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Issues Related to the ATBC Study and CARET |
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The premise that the dosage of -carotene used in the trials was not representative of dietary intake is based on the observation that the dose of
-carotene in the trials was five to 10 times the normal dietary intake (12). This dosing resulted in higher serum concentrations than those reported in observational studies (12,13). At these higher doses, it was suggested,
-carotene would inhibit the absorption of other dietary carotenoids or antioxidants with cancer-protective properties (14), although this hypothesis was subsequently questioned (15). Questions concerning the decision to study subjects at high risk of lung cancer have been addressed by analyses from observational studies reporting an inverse association between
-carotene and lung cancer that also reported that the majority of lung cancer cases in the studies occurred among smokers (8). Moreover, designing randomized clinical chemoprevention trials to test hypotheses in persons at high risk for site-specific cancer is both efficient and desirable. As to study duration, active treatment occurred for an average of 6 and 4 years in the ATBC Study and CARET, respectively. It has been suggested that lag-to-effect and occurrence of events may take substantially longer than 46 years, which raises the possibility that the ATBC Study and CARET underestimated the maximum achievable effects of treatment (16,17).
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Importance of the ATBC Study and CARET |
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Since the ATBC Study and CARET began, an impressive body of knowledge on -carotenes effects has become available that, had it been known in 1985, might have affected the decision to go forward with these trials. For example, as mentioned earlier, supplementation with high doses of
-carotene may affect absorption and plasma concentrations of other carotenoids (20). Moreover, the antioxidant activity of carotenoids can actually cause oxidative stress through pro-oxidant activity, depending on redox potential and biological environment (21). In addition,
-carotene has been shown to have co-carcinogenic effects, possibly by boosting the activity of the phase I enzymes that bioactivate tobacco smoke precarcinogens, such as polycyclic aromatic hydrocarbons (PAH). Individuals with the exon 7 polymorphism of CYP1A1, which encodes a phase I cytochrome P450 enzyme, have higher levels of PAH-DNA adducts and may be particularly susceptible to the co-carcinogenic effects of
-carotene (18).
It is worth noting that the critiques of these trials exemplify a problem common to scientific review of results of completed clinical trials. For both the ATBC Study and CARET, results were reported more than 10 years after initiation of the trials. With results in hand, it is always easier to determine what should have been done. Experimental science today, both physical and theoretical, is far beyond what our capabilities were in 1985. Nevertheless, the results from the ATBC Study and CARET have provided information that may be useful in planning chemoprevention clinical trials of other dietary supplements and in bringing rigorous scientific methodology to the emerging field of complementary and alternative medicine. Results from these trials have also provided important new leads about other cancer risk factors. For example, secondary analyses in the ATBC Study indicated that vitamin E may reduce risk for colorectal and prostate cancer (22), which provided supporting evidence for initiating the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a study designed to determine whether men who take selenium and vitamin E supplements have a lower risk of prostate cancer (23).
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Implications for the Future |
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REFERENCES |
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