SOY ISOFLAVONES AND CELL PROLIFERATION

这一修订提案的长期目标是制定新的 预防结肠癌的营养方法。 拟定研究 涉及非人类灵长类动物，旨在提供数据， 直接支持后续的大豆异黄酮临床研究， 人类 结肠癌发病率的显著差异 西方社会（高发病率）和亚洲国家，如日本（低 发病率）在很大程度上归因于其 可能与大豆的高消费量有关 亚洲国家的蛋白质。 大豆蛋白富含杂环 酚类化合物，称为异黄酮，这是已知的发挥强大的 在体内和体外的抗癌特性。 主要具体 目的是确定大豆异黄酮在饮食水平是否可以达到， 普通美国人结肠细胞增殖减少， 结肠癌风险的中间标志物，在食蟹猴中， 高脂肪饮食。 次要目的是确定大豆异黄酮是否： 1)减少结肠中前列腺素E2的合成，2）增加细胞凋亡 在结肠隐窝上皮中，3）减少雌激素的甲基化 受体基因，以及4）减少粪便胆汁酸分泌。 一个西方 风格，高脂肪饮食含有大豆异黄酮，或控制饮食，将 喂给绝经后的雌猴。 结肠活组织检查 在基线时以及大约4个月和8个月后采集 治疗 所有猴子在治疗12个月后将被安乐死， 并将收集额外的结肠样本进行分析， 乳腺和子宫。 将通过以下方法评估细胞增殖： 增殖细胞核抗原的免疫染色， 细胞将通过详细的组织形态学分析进行定量。 其他测量包括前列腺素、细胞凋亡、雌激素 受体基因甲基化和粪便胆汁酸。 治疗效果将 使用重复测量协方差分析和ANCOVA确定 技术. 这些研究将提供关于潜在的 对结肠细胞增殖的有益作用， 以及结肠癌的其他相关生物风险因素， 独特的猴子模型 如果是积极的，这些数据将有力地支持 未来的人类研究

The long-term objectives of this revised proposal are to devise novel nutritional approaches for colon cancer prevention. The proposed study involves non-human primates and has been designed to provide data to directly support subsequent clinical studies on soy isoflavones in humans. Marked differences in the incidence of colon cancer between Western societies (high incidence) and Asian countries like Japan (low incidence) are attributed in large part to differences in their respective diets and may be related to the high consumption of soy protein in Asian countries. Soy protein is rich in heterocyclic phenolic compounds called isoflavones, which are known to exert potent anticancer properties both in vivo and in vitro. The primary specific aim is to determine if soy isoflavones at dietary levels achievable by the average American reduce colon cell proliferation, an accepted intermediate marker of colon cancer risk, in cynomologus monkeys fed a high-fat diet. Secondary aims are to determine whether soy isoflavones: 1) reduce synthesis of prostaglandin E2 in colon, 2) increase apoptosis in colon crypt epithelium, 3) reduce methylation of the estrogen receptor gene, and 4) reduce fecal bile acid secretion. A western style, high-fat diet containing soy isoflavones, or a control diet, will be fed to surgically postmenopausal female monkeys. Colon biopsies will be collected at baseline and after approximately 4 and 8 months of treatment. All monkeys will be euthanized after 12 months of treatment, and additional colon samples will be collected for analysis, as will mammary gland and uteri. Cell proliferation will be assessed by immunostaining for proliferating cell nuclear antigen, and proliferating cells will be quantified by detailed histomorphometric analysis. Additional measurements include Prostaglandins, apoptosis, estrogen receptor gene methylation, and fecal bile acids. Treatment effects will be determined using repeated measures analysis of covariance and ANCOVA techniques. These studies will provide information on the potential beneficial effects of isoflavones on cell proliferation in colon, as well as other related biological risk factors for colon cancer, in a unique monkey model. If positive, these data will strongly support future studies in humans.