Affiliations of authors: M. Paolini, G. Cantelli-Forti, Department of Pharmacology, Biochemical Toxicology Unit, University of Bologna, Italy; S. Z. Abdel-Rahman, M. S. Legator, Department of Preventive Medicine and Community Health, Division of Environmental Toxicology, The University of Texas, Medical Branch, Galveston.
Correspondence to: Marvin S. Legator, Ph.D., Department of Preventive Medicine and Community Health, Division of Environmental Toxicology, 700 Harborside Dr., University of Texas, Medical Branch, Galveston, TX 775551110 (e-mail: mlegator{at}utmb.edu).
The poor prognosis for many lung cancer patients, despite the increasing efforts for early detection, points to the paramount need for chemopreventive efforts to control this disease. Because of their antioxidant properties, -carotene and other carotenoids have attracted attention as potential chemopreventive agents. Unexpectedly, however, chemoprevention trials, such as ATBC (Alpha-Tocopherol, Beta-Carotene Trial) and CARET (Carotene and Retinol Efficacy Trial), showed that
-carotene, either alone or in combination with vitamins A or E, could actually increase lung cancer incidence and mortality in heavy smokers and asbestos workers (1), suggesting that
-carotene may possess co-carcinogenic properties. As noted by Omenn (2) in a recent editorial in the Journal, the results of these chemopreventive trials emphasize the importance of developing a solid scientific basis, from both in vivo and in vitro mechanistic studies, to guide the selection and use of chemopreventive agents for clinical trials.
In an investigation of the co-carcinogenic properties of -carotene in an animal model, we found that
-carotene supplementation greatly increased the production of cytochrome P450 (CYP) carcinogen-bioactivating enzymes in the lungs. Furthermore, we found that this increased production of CYPs is associated with the generation of oxidative stress (3). Using the BALB/c 3T3 medium-term bioassay, which correlates well (70%85%) with in vivo carcinogenesis, we found that
-carotene markedly enhanced the conversion of both 3-methylcholanthrene and the cigarette smoke carcinogen benzo[a]pyrene to ultimate carcinogens (4). The hypothesis that
-carotene has co-carcinogenic properties is further supported by our recent findings indicating that blocking the increased production of CYPs or the overproduction of reactive oxygen species deprives
-carotene of its detrimental properties (5).
In smokers, oxidative stress could act synergistically with other oxidants contained in cigarette smoke, thus inducing additional genetic damage and imposing a higher risk of cancer. In addition, high levels of CYPs could predispose individuals to a higher risk of cancer because of the increased bioactivation of tobacco smoke procarcinogens. Many of these procarcinogens could also act synergistically with -carotene to increase the production of CYPs and thus to produce a co-carcinogenic effect. This effect could be enhanced in subjects who possess predisposing susceptibility factors, such as polymorphisms (allelic variants) in genes of carcinogen-bioactivation and detoxication enzymes (6), and polymorphisms in genes of DNA repair enzymes (7).
The -carotene story advocates important prerequisites that should be fulfilled before undertaking clinical trials in human subjects. In addition to mechanistic investigations and rigorous toxicologic characterization of the supposed chemopreventive agent, the "genetic make-up" of the trial population should also be considered. The fact that smokers who inherit certain polymorphisms in genes of bioactivating, detoxifying, or DNA repair enzymes may be more susceptible than others could substantially confound the interpretation of the results of a clinical trial. In the meantime, the high fruit and vegetable intake recommendations from both public health agencies and the scientific community should continue to be encouraged, as well as efforts targeting smoking cessation. As argued above, there are strong scientific reasons to suspect that it may be naive, and possibly dangerous, to base cancer chemoprevention on the selective administration of only one or even a few chemicals.
REFERENCES
1
Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:11505.
2
Omenn GS. Chemoprevention of lung cancer is proving difficult and frustrating, requiring new approaches. J Natl Cancer Inst 2000;92:95960.
3 Paolini M, Cantelli-Forti G, Perocco P, Pedulli GF, Abdel-Rahman SZ, Legator MS. Co-carcinogenic effect of beta-carotene. Nature 1999;398:7601.[Medline]
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5
Perocco P, Mazzullo M, Broccoli M, Rocchi P, Ferreri AM, Paolini P. Inhibitory activity of vitamin E and -naphthoflavone on beta-carotene-enhanced transformation of BALB/c 3T3 cells by benzo(a)pyrene and cigarette-smoke condensate. Mutat Res 2000;465:1518.[Medline]
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Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 2000;9:328.
7 Abdel-Rahman SZ, El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett 2000;159:6371.[Medline]
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