Strategies for cancer prevention involving reduction or elimination of human exposure to environmental carcinogens may not always be possible. Inhibition of the development of cancer by the administration of anticarcinogenic agents may offer a practical alternative for reducing human cancer burden. However, the successful utilization of chemoprotective interventions will require solid mechanistic understanding of the action(s) of these agents. The proposed study will continue to investigate the modes of protection afforded by oltipraz and other 1,2-dithiole-3-thiones on aflatoxin B1 hepatocarcinogenesis in the rat. Oltipraz is an effective and potent inhibitor of experimental carcinogenesis in may tissues and holds strong promise for use in human interventions. Specifically, we will investigate the chemistry of dithiolethiones with respect to (a) new methods for synthesis of these related molecules; (b) synthesis of compounds designed to test emerging structure-activity relationships, leading to more active compounds; (c) synthesis of oltipraz metabolites for evaluation in bioassays; (d) synthesis of radiolabeled dithiolethiones for mechanistic studies; and (e) synthesis of dithiolethiones suitable for production of antibodies. We will also investigate the structure-activity relationships of the synthesized compounds on (a) phase I & II enzyme activities; (b) mechanisms of induction of phase II enzymes: (c) altered carcinogen-DNA adduct formation; and (d) inhibition of AFB1-induced tumorigenesis in rats. Finally, we will utilize a molecular genetic approach to identify and characterize the spectrum of genes induced by dithiolethiones in rat liver. A cDNA library prepared from the livers of rats treated with 1,2- dithiole-3-thione will be screened by differential/subtractive hybridization techniques. Isolated clones will then be identified and characterized by hybridization and DNA sequence analyses. Collectively, these multifaceted, integrated studies will more fully define the chemical, molecular, biochemical and biological mechanisms of action of this of this versatile class of chemoprotective agents. The long term goal of this work is to facilitate the most efficient and effective use dithiolethiones as protective agents in human populations exposed to environmental toxicants.
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