ARACHIDONIC ACID METABOLISM AND CANCER CHEMOPREVENTION

大鼠乳腺中的肿瘤发展受到以下因素的影响： 花生四烯酸代谢物（类花生酸）的调节。 花生四烯酸代谢的几种途径的修饰剂是 乳腺癌发生的有效抑制剂和类二十烷酸 已被提议作为增强乳腺癌的介质， 饮食脂肪诱发癌症。 该研究计划描述了 在本提案中， 类花生酸在乳腺癌发生中的作用，特别强调 花生四烯酸代谢的改变作为 乳腺癌化学预防 的总体目标 建议的方案是：（a）确定具体途径， 花生四烯酸代谢产物，可以调节 （B）研究大鼠乳腺中的肿瘤发展; 类二十烷酸作为膳食脂肪作用介质的作用 乳腺上皮;和（c）基于这些结果， 研究，开发乳腺癌化学预防方案， 功效与毒性比上级于目前可获得的那些。 将使用体外/体内联合方法来解决这些问题 问题. 为了确定具有最大活性的方案， 按花生四烯酸代谢的特定途径，研究 将进行测定药理学的影响 对大鼠原代培养物中类花生酸生物合成的影响 乳腺上皮细胞 这些实验还将解决 可能限制抗癌功效， 花生四烯酸代谢的重新定向。 其他研究 将研究脂肪酸对类花生酸的影响， 花生四烯酸的生物合成，以及花生四烯酸修饰剂的作用 代谢对脂肪酸的作用。 这些体外结果将 将其整合到体内治疗方案的设计中 致癌实验，目标是：（a）开发非 毒性化学预防方案， 活性;（B）定义各种途径之间的相互作用， 花生四烯酸代谢与乳腺癌的关系 诱导;以及（c）确定类花生酸的可能作用 膳食脂肪在乳腺癌中的作用机制 致癌作用

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.