ARACHIDONIC ACID METABOLISM AND CANCER CHEMOPREVENTION

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Breast cancer remains the leading cause of cancer morbidity and mortality in American women aged 15 to 74 years. Thus, in addition to traditional therapeutic modalities, new strategies for breast cancer prevention are called for in the attempt to control the disease. These strategies, which seek to inhibit breast cancer induction during the preneoplastic period, can have a variety of mechanistic bases, including the differential biology of normal and neoplastic cells. Arachidonic acid metabolism is increased in many neoplastic tissues, including experimental and human mammary carcinomas. As a result, levels of several arachidonic acid metabolites (eicosanoids) are increased in mammary cancers as compared to normal mammary gland. Modulation of arachidonic acid metabolism with the prostaglandin synthetase inhibitors indomethacin and flurbiprofen results in a significant inhibition of mammary cancer induction in rats exposed to a chemical carcinogen. However, since inhibition of prostaglandin synthetase inhibits the production of many eicosanoids, the role of specific pathways of arachidonic acid metabolism in carcinogenesis is unknown. To address this issue, studies are proposed in which inhibitors of specific enzymes in the arachidonic acid cascade will be administered to rats previously exposed to the mammary carcinogen N-methyl-N-nitrosourea. The effects of these agents on mammary cancer incidence, tumor multiplicity, and tumor latency will be determined to assess their efficacy as inhibitors of carcinogenesis. Furthermore, the modifying effect of dietary fat on this inhibition will be examined. In this manner, the role of specific pathways of arachidonic acid metabolism in mammary carcinogenesis can be determined, and the utility of modulation of eicosanoid biosynthesis as an avenue for cancer prevention can be explored.