A growing body of evidence points to the importance of exogenous rather than constitutional factors in the genesis of the majority of human malignancies. As such, carcinogenesis induced by environmental agents should be amenable to interruption or reversal by chemoprotective interventions. It is the objective of this project to develop novel methods for protection of tissues against carcinogenic agents by examining the molecular mechanisms involved in the anticarcinogenic action of antioxidants. Antioxidants have two major modes of action: (1) inducers of carcinogen detoxication enzymes and (2) free radical scavengers. These mechanisms will be examined in two model systems for experimental carcinogenesis. First, the mechanism of protective action of dietary antioxidants (butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin, and 1,2-dithiol-3-thione) on aflatoxin Bl hepatocarcinogenesis in the rat will be investigated. The effects of dietary antioxidants on: a) quantitative and qualitative patterns, organ specificity, and repair of aflatoxin-DNA adduct formation and removal, b) enzymologic basis for the altered balance between aflatoxin activation and detoxication and the effects on the kinetics of aflatoxin elimination, and c) induction of gamma glutamyltranspeptidase positive foci, a short-term in vivo model - for aflatoxin carcinogenesis, will be determined. Second, the role of free radicals in tumor promotion will be assessed by developing strategies for the direct measurement of these species using electron paramagnetic resonance and hplc techniques in target cells. Radicals generated following promoter exposure will be identified and quantified in both primary murine epidermal cells and the JB6 epidermal cell line. Sensitivity of these responses to antioxidant scavengers and detoxifiers will also be defined. These systematic approaches are designed to integrate biochemical and biological responses and should lead to better understanding of antioxidant mechanisms for the inhibition of carcinogenesis and facilitate insights into how dietary constituents may modulate the risk of populations to environmentally occurring carcinogens and promoters. Additionally, this RCDA award will provide the principle investigator the opportunity to extend and enrich his training in the field of chemical carcinogenesis; specifically, the areas of 1) the enzymologic basis for carcinogen detoxication and 2) oxygen radicals and tumor promotion.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Modified Research Career Development Award (K04)
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Chemical Pathology Study Section (CPA)
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Johns Hopkins University
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Kensler, T W; Davidson, N E; Groopman, J D et al. (1993) Chemoprotection by inducers of electrophile detoxication enzymes. Basic Life Sci 61:127-36
Groopman, J D; DeMatos, P; Egner, P A et al. (1992) Molecular dosimetry of urinary aflatoxin-N7-guanine and serum aflatoxin-albumin adducts predicts chemoprotection by 1,2-dithiole-3-thione in rats. Carcinogenesis 13:101-6
Kensler, T W; Groopman, J D; Eaton, D L et al. (1992) Potent inhibition of aflatoxin-induced hepatic tumorigenesis by the monofunctional enzyme inducer 1,2-dithiole-3-thione. Carcinogenesis 13:95-100
Akman, S A; Doroshow, J H; Kensler, T W (1992) Copper-dependent site-specific mutagenesis by benzoyl peroxide in the supF gene of the mutation reporter plasmid pS189. Carcinogenesis 13:1783-7
Roebuck, B D; Liu, Y L; Rogers, A E et al. (1991) Protection against aflatoxin B1-induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz): predictive role for short-term molecular dosimetry. Cancer Res 51:5501-6
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Davidson, N E; Egner, P A; Kensler, T W (1990) Transcriptional control of glutathione S-transferase gene expression by the chemoprotective agent 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) in rat liver. Cancer Res 50:2251-5
Swauger, J E; Dolan, P M; Kensler, T W (1990) Role of free radicals in tumor promotion and progression by benzoyl peroxide. Prog Clin Biol Res 340D:143-52
Taffe, B G; Zweier, J L; Pannell, L K et al. (1989) Generation of reactive intermediates from the tumor promoter butylated hydroxytoluene hydroperoxide in isolated murine keratinocytes or by hematin. Carcinogenesis 10:1261-8
Liu, Y L; Roebuck, B D; Yager, J D et al. (1988) Protection by 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) against the hepatotoxicity of aflatoxin B1 in the rat. Toxicol Appl Pharmacol 93:442-51

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