P1 - Omega-3 fatty acids and Colorectal Cancer Prevention

项目1 有必要确定和开发更有利的基于治疗指数的癌症预防措施 干预措施。这个项目的总体目标是测试用iu3脂肪酸代替106 大肠粘膜中的脂肪酸将充分改变二十碳五烯酸(EPA)的比例 使花生四烯酸(AA)可用于前列腺素H合成酶(PGHS)-1和2的局部还原 前列腺素(PG)E_2浓度。结肠粘膜前列腺素E_2的减少将减少癌变 应激并最终减少结肠上皮中肿瘤的发展。我们还假设 可以通过血浆EPAiAA比率来预测足以降低局部PGE2的鱼油剂量，因此可以 个性化。前列腺素E_2浓度的降低足以减少增殖并增强 可以寻找大肠粘膜隐窝的细胞凋亡。目标1将定义饮食的剂量反应 小鼠鱼油及其还原后血浆和结肠粘膜EPA/AA比值的关系 PGHS-1和pGHS-2野生型小鼠结肠粘膜中前列腺素E_2的含量 人类的脂肪酸摄入量。血浆和结肠EPA/AA比值及前列腺素E_2浓度的变化 对结肠粘膜和尿液进行化验。目标1中的数据是定义第一阶段设计所必需的 AIM 2中建议的临床试验。临床试验将确定在人类体内补充鱼油是否对 正常饮食可以产生结直肠粘膜和血浆EPAiAA比率，在小鼠模型中定义 会降低大肠粘膜PGE2，降低大肠隐窝增殖指数，促进细胞凋亡 附属品。贝叶斯驱动的生物标志物自适应第一阶段设计基于个体的个体化剂量 生物标志物反应。该项目获得的数据将决定该项目的可行性、未来的设计和 U)3脂肪酸作为结直肠癌潜在预防药物的II期临床试验的生物标志物终点 腺癌。

Project 1 There is a need to identify and develop more favorable therapeutic index-based cancer preventive interventions. The overall goal of this project is to test the hypothesis that substituting iu3 fatty acids for 106 fatty acids in colorectal mucosal membranes will sufficiently modify the ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) available to prostaglandin-H synthases (PGHS)-1 and 2 to reduce local prostaglandin (PG)E2 concentrations. Reduction of colonic mucosal PGE2 will reduce the carcinogenesis stress and ultimately reduce the development of neoplasia in the colonic epithelium. We also hypothesize that the dose of fish oil sufficient to reduce local PGE2 can be predicted by plasma EPAiAA ratio and thus be individualized. The reduction of PGE2 concentrations sufficient to reduce proliferation and enhance apoptosis of the colorectal mucosal crypt may be searched. Aim #1 will define tlie dose response to dietary fish oil in mice and the relationshipo between the plasma and colonic mucosal EPA:AA ratio upon reduction of PGE2 in colonic mucosa of PGHS-1 and -2 wild type mice will be fed diets formulated to match multiple human fatty acid intakes. The plasma and colonic mucosal EPA:AA ratios and PGE2 concentrations in colonic mucosa and urine will be assayed. Data in Aim 1 are necessary to define the design of a Phase I clinical trial proposed in Aim 2. The clincal trial will determine if fish oil supplementation in humans on a normal diet can produce a colorectal mucosal and plasma EPAiAA ratio defined in the mouse models that will reduce colorectal mucosal PGE2, reduce colorectal crypt proliferation index and enhance apoptosis indicies. A Bayesian driven biomarker adaptive phase I design individualizes dose on the basis of individual biomarker response. The data obtained in this project will determine the feasibility, future design and biomarker endpoints of Phase II clinical trials of u)3 fatty acids as potential preventives of colorectal adenocarcinoma.