AGENTS AND MECHANISMS OF TUMOR PREVENTION IN THE MIN MODEL OF FAP

该项目的最终目标是确定安全的化学预防措施。 降低散发性结直肠肿瘤发病率和死亡率的药物 并提供了对遗传和分子原因的基本见解 腺瘤-癌序列。我们将评估代理并描述其特征 多发性肠道肿瘤(MIN)小鼠模型的作用机制 家族性腺瘤性息肉病(FAP)患者。MIN小鼠与FAP 患者有腺瘤性息肉病(APC)基因胚系突变 因此是体细胞APC突变的理想模型 用于启动零星的结直肠肿瘤。 我们项目的具体目标是：L。精挑细选 环氧合酶(COX-2)抑制剂SC-58635和SC-49046对MIN小鼠和 评估肿瘤预后和合适的生物标记物。作为主要终端，我们 将评估肿瘤的数量。肿瘤的大小，COX-2的表达， 前列腺素水平、上皮细胞增殖率和细胞凋亡指数 也将被确定。2.管理组胺2型(H2)受体 阻滞剂西咪替丁对MIN小鼠的作用及评价肿瘤转归的适宜条件 生物标志物。作为主要终点，我们将评估肿瘤的数量。大小 肿瘤、组胺水平、肿瘤浸润性疾病的数量和类型 淋巴细胞，细胞因子谱，粘膜DNA加合物，血清胃泌素， 上皮细胞增殖率和凋亡指数也将 下定决心。我们将西咪替丁与其他H2阻滞剂(雷尼替丁)进行比较 和法莫替丁)以及质子泵抑制剂奥美拉唑。3. 给MIN小鼠两种候选化学预防药物的联合用药 在特定目标#1中确定具有不同作用机制的药物 和#2，并评估肿瘤预后和相关生物标记物。4. 急性呼吸窘迫综合征患者应用候选化学预防制剂S的研究 随机、舒林酸对照、双盲、交叉试验 通过视频内窥镜连续监测息肉数量。我们还将 连续评估腺瘤的息肉大小和适当的生物标志物 大肠粘膜。

The ultimate goal of this project is to identify safe chemopreventive agents to reduce morbidity and mortality from sporadic colorectal neoplasia and provide basic insights into the genetic and molecular causation of the adenoma-carcinoma sequence. We will evaluate agents and characterize their mechanisms of action in the multiple intestinal neoplasia (MIN) mouse model and patients with familial adenomatous polyposis (FAP). MIN mice and FAP patients have germline mutation of the adenomatous polyposis col (APC) gene and are therefore ideal models for the somatic APC mutations responsible for initiation of sporadic colorectal tumors. The specific aims of our project are: l. Administer the selective cyclooxygenase (COX-2) inhibitors SC-58635 and SC-49046 to MIN mice and evaluate tumor outcome and appropriate biomarkers. As primary endpoint we will assess numbers of tumors. Sizes of tumors, COX-2 expression, prostaglandin levels, epithelial proliferation rates, and apoptotic indices will also be determined. 2. Administer the histamine type 2 (H2) receptor blocker cimetidine to MIN mice and evaluate tumor outcome and appropriate biomarkers. As primary endpoint we will assess numbers of tumors. Sizes of tumors, histamine levels, numbers and types of tumor-infiltrating lymphocytes, cytokine profiles, mucosal DNA adducts, serum gastrin, epithelial proliferation rates, and apoptotic indice will also be determined. We will compare cimetidine to other H2 blockers (ranitidine and famotidine) and to the proton pump inhibitor omeprazole. 3. Administer to MIN mice a combination of two candidate chemopreventive agents with different mechanisms of effects identified in Specific Aims #1 and #2 and evaluate tumor outcome and associated biomarkers. 4. Administer candidate chemopreventive agent(s) to FAP patients in a randomized, sulindac-controlled, double-blinded, crossover trial and sequentially monitor for polyp number by video endoscopy. We will also sequentially assess polyp size and appropriate biomarkers in adenomas and colorectal mucosa.