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 age may offer a practical alternative for reducing human cancer burden. However, the successful utilization of chemopreventive interventions will require solid mechanistic understanding of the action(s) of these agents. The proposed studies will continue to investigate the modes of protection afforded by oltipraz and other 1,2-dithiole-3-thiones on aflatoxin (AFB1) hepatocarcinogenesis in the rat. Oltipraz is an effective and potent inhibitor of experimental carcinogenesis induced by many agents in many tissues. Oltipraz is currently being evaluated in Phase I and II clinical chemoprevention trials. This project will continue the development and evaluation of dithiolethiones more active than oltipraz on a) inhibition of AFB1-induced tumorigenesis in rats; b) altered AFB- DNA adduct formation; and c) induction of carcinogen detoxication ("phase 2") enzymes. Using a large series of analogs synthesized previously, the structure-activity relationships for inhibition of cytochrome P450 activation of AFB1 metabolism will also be determined. Using molecular genetic approaches, the identification and characterization of genes induced by dithiolethiones in rat liver will be continued together with elucidation of the role(s) of these gene products in protection against aflatoxin toxicity and carcinogenicity. Several novel inducible genes recently identified may protect against inflammation and oxidative stress. Finally, the chemopreventive actions and efficacy of oltipraz will be evaluated in a unique experimental model, the tree shrew, in which infection with human hepatitis B virus and exposure to AFB1 synergistically enhance the incidence of liver cancer, as occurs in humans. Collectively, these multifaceted, integrated studies will more fully define the chemical, molecular, biochemical and biological mechanisms of action of this versatile class of chemoprotective agents. The long-term goal of this project is to facilitate the most efficient and effective use dithiolethiones as protective agents in human populations exposed to environmental toxicants.
NIH ExPorter
NIH ExPorter