SOY ISOFLAVONES AND CELL PROLIFERATION

这项修订提案的长期目标是设计出新颖的 预防结肠癌的营养方法。建议进行的研究 涉及非人类灵长类动物，并被设计为向 直接支持大豆异黄酮类的后续临床研究 人类。结肠癌发病率的显著差异 西方社会(发病率高)和亚洲国家，如日本(低发病率) 发病率)在很大程度上归因于 各自的饮食习惯，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 被称为异黄酮类的酚类化合物，已知能有效地 体内和体外的抗癌性能。主要的具体内容 目的是确定大豆异黄酮在饮食水平上是否可以通过 一个公认的结论是，普通美国人减少结肠细胞的增殖 食蟹猴患结肠癌风险的中间标志 高脂肪饮食。次要目标是确定大豆异黄酮是否： 1)减少结肠中前列腺素E_2的合成，2)增加细胞凋亡 在结肠隐窝上皮，3)减少雌激素的甲基化 4)减少粪便胆汁酸的分泌。西部片 风格，含有大豆异黄酮的高脂肪饮食，或对照饮食，将 被喂给手术后绝经的雌性猴子。结肠活组织检查将 在基线和大约4个月和8个月后收集 治疗。所有猴子将在12个月的治疗后被安乐死， 并将收集更多的结肠样本进行分析， 乳腺和子宫。细胞增殖将通过以下方式进行评估 增殖细胞核抗原免疫组织化学染色及增殖 细胞将通过详细的组织形态计量学分析进行量化。 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 用重复测量的协方差分析和方差分析来确定 技巧。这些研究将提供潜在的信息 异黄酮类化合物对大鼠结肠癌细胞增殖的促进作用 以及其他与结肠癌相关的生物学风险因素，在 独特的猴子模型。如果是正面的，这些数据将有力地支持 未来对人类的研究。

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.