ANTICARCINOGENIC EFFECTS AND MECHANISMS OF GENISTEIN

流行病学研究表明，豆类食品与 消费和人类癌症死亡率。实验室研究表明， 大豆饮食也能抑制实验诱导的动物肿瘤。虽然 大多数研究将大豆的抗癌作用归因于 蛋白酶抑制剂，越来越多的证据表明，异黄酮类，非 大豆中丰富的蛋白质成分也可能起到重要作用 角色。染料木素是主要的大豆异黄酮之一，已被证明具有 抑制酪氨酸蛋白激酶(TPK)、DNA拓扑异构酶II(Topo Il)，以及 核糖体S6激酶(RS6K)，抑制肿瘤细胞生长，诱导 几种恶性细胞系的分化。我们的初步研究 已经证明染料木素抑制7，12-二甲基苯并[a]菲 (DMBA)诱导DNA加合物形成和DNA氧化，并抑制12-O- 十四酰佛波醇-13-乙酸酯(TPA)诱导的过氧化氢生成， 炎症反应和体内原癌基因的表达。然而， 金雀异黄素是否能改变体内的化学致癌作用 不清楚。这项提议旨在检验金雀异黄素 抑制致癌物质诱导的DNA氧化损伤，并进一步 修改以下项目的启动、提升和进展过程 化学致癌。总体目标是确定是否 金雀异黄素改变启动和促进相关的生化 从而抑制体内皮肤肿瘤的形成。首字母 该项目的目的是确定金雀异黄素的局部应用 修改与启动和促销相关的事件，重点放在 氧化DNA损伤。第二个目标是确定是否有针对性的 金雀异黄素的应用影响启动、促进和/或进展 多阶段皮肤癌。最后，我们将确定饮食是否 金雀异黄素对小鼠脑内这些致癌过程的调节 多阶段致癌模型。事实上，如果金雀异黄素 金雀异黄素的抗癌作用及其作用机制 这将有助于大豆异黄酮在我国的应用。 预防和/或治疗人类癌症。

Epidemiological studies suggest an inverse correlation between soyfood consumption and human cancer mortality. Laboratory studies indicate that soy diets also inhibit experimentally induced animal tumors. Although most studies attribute the anticarcinogenic effect of soybeans to the protease inhibitors, increasing evidence suggests that isoflavones, non- protein components richly present in soybeans, may also play important roles. Genistein, one of the major soybean isoflavones, has been shown to inhibit tyrosine protein kinase (TPK), DNA topoisomerase II (Topo Il), and ribosomal S6 kinase (RS6K), suppress tumor cell growth, and induce differentiation of several malignant cell lines. Our preliminary studies have shown that genistein suppresses 7,12-dimethylbenz[a]anthracene (DMBA)-induced DNA adduct formation and DNA oxidation, and inhibits 12-O- tetradecanoyl phorbol-13-acetate (TPA)-induced H2O2 formation, inflammatory responses, and proto-oncogene expression in vivo. However, whether genistein modifies chemical carcinogenesis in vivo remains unclear. This proposal is designed to test the hypothesis that genistein inhibits oxidative DNA damage induced by carcinogenic agents and further modifies the initiational, promotional, and progressional processes of chemical carcinogenesis. The overall objective is to determine if genistein modifies the initiation- and promotion-related biochemical events and subsequently inhibits skin tumor formation in vivo. The initial aim of the project is to determine if topical application of genistein modifies the initiation- and promotion-related events with an emphasis on oxidative DNA damage. The second aim is to determine if topical application of genistein affects initiation, promotion and/or progression of multistage skin carcinogenesis. Finally, we will determine if dietary administration of genistein modulates these carcinogenic processes in the multistage carcinogenesis model. If, in fact, genistein has anticarcinogenic effects, an elucidation of the mechanisms of genistein's action will contribute to application of this soybean isoflavone in prevention and/or therapy of human cancers.