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 chemopreventive interventions will require solid mechanistic understanding of the action(s) of these agents. Dithiolethiones are amongst the most broadly effective classes of chemopreventive agents in experimental models; clinical trials also indicate their efficacy in populations exposed to dietary aflatoxins or tobacco smoke. The objectives of this investigation remain to define the mechanisms of chemoprevention afforded by dithiolethiones and related compounds. Highly quantitative animal model systems for interrelating the molecular, biochemical, and biological actions of these chemopreventive agents have been developed and will be used in i) the development and characterization of new, potent dithiolethiones, ii) the identification of novel genes modulated by dithiolethiones, iii) probing the specific contributions of these induced genes to chemoprevention, and iv) the validation of intermediate biomarkers to assess the efficacy of anticarcinogenic interventions. Recent gene discovery activities indicate that dithiolethiones affect the expression of many genes that are likely to repress the cytotoxic and autopromoting actions of carcinogens in addition to their genotoxic ones. Thus, investigations of the cytoprotective mechanisms of dithiolethiones form the primary focus of this renewal. Functional consequences of induction of protective pathways by dithiolethiones, including STAT signaling, proteasome activation, and carcinogen metabolism by aldehyde reductases, will be probed through a series of in vitro assays and studies in transgenic animals using a panel of validated intermediate biomarkers. Structure-activity studies of a large dithiolethione library will probe their tissue and cell-type specific pharmacodynamic action in a reporter mouse to better inform matching of agents with target tissues. This library will also be screened for analogs in addition to oltipraz that inhibit and reverse the development of fibrosis and cirrhosis, a key step in liver cancer. Collectively, these studies will further the goal of effectively using dithiolethiones as protective agents in human populations exposed to environmental toxicants.
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