? ? Colon cancer is one of the most common forms of cancer in the Western world. The colon is constantly exposed to a variety of environmental contaminants, through smoking, diet, and pollution, which may initiate carcinogenesis. One such environmental contaminant is benzo[a]pyrene, a polycyclic aromatic hydrocarbon that is present in tobacco smoke and in cooked meat. Central to the detoxification of benzo[a]pyrene and other environmental carcinogens is a series of metabolizing enzymes in the liver and the colon that render the carcinogen more easily excreted. Modulation of the activity and expression of these metabolic enzymes would increase the capacity of cells to detoxify environmental carcinogens, preventing them from damaging DNA and transforming normal colon epithelial cells into tumor cells. Despite its prevalence, epidemiologic and experimental data demonstrate that colon cancer is highly preventable. One promising colon chemopreventive agent is sulindac, a non-steroidal anti-inflammatory drug (NSAID) routinely prescribed to alleviate chronic pain and inflammation. Sulindac has been shown to inhibit colon cancer in humans and chemically-induced carcinogenesis in animal models. Given the importance of carcinogen-metabolizing enzymes in preventing carcinogenesis, we propose to investigate the effect of sulindac on the activity and expression of this critical series of enzymes. Four cell lines, 3 human and one mouse, representing the liver and the colon will be used as in vitro models, and A/J mice will be used for in vivo studies. The effect of sulindac and its derivative, sulindac sulfide, on the activity of three carcinogen- metabolizing enzymes, cytochrome P450 1A1, quinone reductase, UDP- glucuronosyltransferase 1A1, and glutathione-S-transferase, will be investigated in these models. These studies will establish a novel biochemical and molecular target of sulindac and further our understanding of the mechanisms by which it prevents colon cancer. These experiments may also aid in designing novel and more effective chemopreventive agents to alleviate the pain and suffering due to colon cancer. ? ? ?
