MECHANISMS OF CHEMOPROTECTION BY OLTIPRAZ

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The prevention of cancer is an urgent and promising direction of biological research. Dietary factors are believed to account for as much as one-third of the annual incidence of cancer. Though the underlying biochemical mechanisms are controversial, strong associations with dietary mutagen intake and the risk of colon cancer have been presented. Dietary constituents associated with a lowered incidence of cancer include broccoli, Brussels sprouts, cauliflower and cabbage. These vegetables are characterized by high levels of dithiolethiones and other substances. Oltipraz, a synthetic dithiolethione, is the lead compound in the development of novel chemopreventive agents that may protect against mutagenesis. It has been proposed that oltipraz functions by elevating the activities of Phase II detoxicating enzymes (including DT-diaphorase), primarily through the induction of transcriptional activity. While we and others have shown that transcriptional induction through a number of cis-acting elements (including AP-1 and NF-kappaB), may account for the upregulation in detoxicating enzyme activity, the basis for oltipraz's effects on transactivating factors remains unknown. Furthermore, we have recently presented evidence that suggests an alternative mechanisms of action, by demonstrating that oltipraz induces the repair of DNA adducts, a process that occurs primarily by nucleotide excision repair. We postulate that both of these mechanisms may act to protect normal cells, and therefore we propose to perform a detailed analysis of these actions at a molecular level. Our specific aims are: 1) To determine the basis for the transcriptional activation of DT-diaphorase induced by oltipraz, and 2) To determine the basis for the stimulation of DNA repair by oltipraz. We will also screen a series of dithiolethione analogues for their ability to induce NER activity. The results of these studies will enable the design of more selective and less toxic chemopreventive agents.