ARACHIDONIC ACID METABOLISM AND CANCER CHEMOPREVENTION

大鼠乳腺中的肿瘤发育受制于 花生四烯酸(二十碳二烯酸)代谢产物的调节。 花生四烯酸代谢的几个途径的修饰剂是 有效的乳腺癌发生抑制剂和二十烷类化合物 已被认为是增强乳房功能的媒介 由饮食脂肪引起的致癌。所描述的研究计划 在本提案中，力求进一步界定 二十烷类化合物在乳腺癌发生中的作用，特别强调 花生四烯酸代谢的修饰作为一种机制 乳腺癌的化学预防。该计划的总体目标 拟议的方案是：(A)确定具体路径和 花生四烯酸代谢产物可调节 大鼠乳腺肿瘤的发生；。(B)研究 二十烷基类化合物作为膳食脂肪作用的中介在 乳腺上皮细胞；以及(C)根据这些结果 研究，开发乳腺癌化学预防方案 药效与毒性的比率优于目前可用的。 将使用体外和体内相结合的方法来解决这些问题 问题。为了确定具有最大活性的方案-- 花生四烯酸代谢的特定途径，研究 将进行以确定药理作用的影响 大鼠原代培养中二十烷类化合物生物合成的研究 乳腺上皮细胞。这些实验还将解决 抗癌疗效可能因以下原因而受到限制 花生四烯酸代谢的重定向。其他研究 将研究脂肪酸对二十烷类化合物的影响 花生四烯酸的生物合成及其修饰剂的影响 代谢对脂肪酸的作用。这些体外实验结果将会 被整合到体内协议的设计中 致癌实验，目标是：(A)开发非 增加抗癌作用的中毒性化学预防方案 活动；(B)界定各种途径之间的相互作用 花生四烯酸代谢在乳腺癌调控中的作用 以及(C)确定二十烷类化合物的可能作用 乳房膳食脂肪作用机制中的生物合成 致癌。

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.