ANTICARCINOGENIC EFFECTS AND MECHANISMS OF GENISTEIN

流行病学研究表明，大豆食品 消费和人类癌症死亡率。实验室研究表明， 大豆饮食还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， 大豆中富含的蛋白质成分， 角色染料木黄酮是主要的大豆黄酮之一， 抑制酪氨酸蛋白激酶（TPK）、DNA拓扑异构酶II（Topo II）， 核糖体S6激酶（RS6 K），抑制肿瘤细胞生长，并诱导 几种恶性细胞系的分化。我们的初步研究 已经表明染料木黄酮抑制7，12-二甲基苯并[a]蒽 DMBA诱导的DNA加合物形成和DNA氧化，并抑制12-O- 十四烷酰基佛波醇-13-乙酸酯（TPA）诱导的H2 O2形成， 炎症反应和体内原癌基因表达。 然而，在这方面， 染料木黄酮是否能改变体内化学致癌作用， 不清楚这项提议旨在检验染料木黄酮 抑制由致癌剂诱导的氧化性DNA损伤， 修改的初始化，促进，和渐进的过程， 化学致癌作用 总体目标是确定 染料木黄酮修饰与启动和促进相关的生化 事件并随后抑制体内皮肤肿瘤形成。初始 该项目的目的是确定局部应用染料木黄酮 修改了与入会和晋升有关的活动，重点是 氧化性DNA损伤第二个目的是确定是否局部 染料木黄酮的应用影响起始、促进和/或进展 多阶段皮肤癌发生。最后，我们将确定饮食是否 染料木黄酮的给药调节这些致癌过程， 多阶段致癌模型如果染料木黄酮 金雀异黄素抗癌作用机制的研究 此举将有助于该大豆异黄酮在食品工业中的应用 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.