ARACHIDONIC ACID METABOLISM AND CANCER CHEMOPREVENTION

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Neoplastic development in the rat mammary gland is subject to regulation by metabolites of arachidonic acid (eicosanoids). Modifiers of several pathways of arachidonic acid metabolism are effective inhibitors of mammary carcinogenesis, and eicosanoids have been proposed as mediators of the enhancement of mammary cancer induction by dietary fat. The research program described in the present proposal seeks to define further the role of eicosanoids in mammary carcinogenesis, with specific emphasis on the modification of arachidonic acid metabolism as a mechanism for mammary cancer chemoprevention. The overall objectives of the proposed program are: (a) to identify specific pathways and products of arachidonic acid metabolism which can regulate neoplastic development in the rat mammary gland; (b) to study the role of eicosanoids as mediators of dietary fat action in the mammary epithelium; and (c) on the basis of the results of these studies, to develop mammary cancer chemoprevention regimens with efficacy to toxicity ratios superior to those presently available. A combined in vitro/in vivo approach will be used to address these issues. In order to define regimens with maximal activity in sup- pressing specific pathways of arachidonic acid metabolism, studies will be conducted to determine the influence of pharmacologic agents on eicosanoid biosynthesis in primary cultures of rat mammary epithelial cells. These experiments will also address possible limitations to anticarcinogenic efficacy as a result of redirection of arachidonic acid metabolism. Additional studies will investigate the influence of fatty acids on eicosanoid biosynthesis, and the effects of modifiers of arachidonic acid metabolism on fatty acid action. These in vitro results will then be integrated into the design of protocols for in vivo carcinogenesis experiments, with the goals of: (a) developing non- toxic chemoprevention regimens with increased anticarcinogenic activity; (b) defining the interactions among various pathways of arachidonic acid metabolism in the modulation of mammary cancer induction; and (c) determining the possible role of eicosanoid biosynthesis in the mechanism of dietary fat action in mammary carcinogenesis.