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 chemicals 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 of these agents. The proposed study will investigate the modes of protection afforded by dietary 1, 2- dithiole-3-thiones, reported constituents of cruciferous vegetables, on aflatoxin Beta 1 hepatocarcinogenesis in the rat. Previous studies from our laboratories have demonstrated that dietary antioxidants, including 1, 2-dithiole-3-thiones, block chemical carcinogenesis at this target site. Evidence to date suggests that dietary antioxidants induce the activities of carcinogen detoxication enzymes to result in lower levels of DNA adduct formation and enhanced carcinogen elimination. The proposed will extend these studies by 1) synthesizing a series of rationally-designed analogues of 1, 2- dithiole-3-thione; 2)evaluating the spectrum of actions and mechanisms of these compounds on the induction of Phase I and II enzymes and reduction in carcinogen-DNA adducts; 3) examining the chemoprotective actions of the newly synthesized dithiolthiones as inhibitors of gamma glutamyltranspeptidase positive lesions, a short-term model for aflatoxin carcinogenesis, as well as hepatic cancers; and, 4) utilizing the dithiolthione/aflatoxin chemoprotection model to develop and validate biomarkers for assessing both risk from carcinogen exposure and the efficacy of anticarcinogen intervention. The long term goal of this work is to facilitate our understanding of how dietary constituents may modulate the target organ risk in human populations exposed to naturally-occurring carcinogens.
Showing the most recent 10 out of 116 publications
