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药物 降低散发性结肠直肠瘤形成发病率和死亡率的药物 并提供基本的见解，遗传和分子的原因， 腺瘤-癌序列 我们将评估代理商，并描述他们的 多发性肠肿瘤（MIN）小鼠模型中的作用机制 和家族性腺瘤性息肉病（FAP）患者。MIN小鼠和FAP 患者存在腺瘤性息肉病col（APC）基因的生殖系突变 因此是体细胞APC突变的理想模型 散发性结直肠肿瘤的起始。 我们项目的具体目标是：l。 管理选择性 环氧化酶（考克斯-2）抑制剂SC-58635和SC-49046给MIN小鼠， 评估肿瘤结果和适当的生物标志物。 作为主要终点，我们 将评估肿瘤的数量。 肿瘤大小，考克斯-2表达， 前列腺素水平、上皮细胞增殖率和凋亡指数 也将被确定。 2. 给予组胺2型（H2）受体 阻断剂西咪替丁MIN小鼠，并评估肿瘤结果和适当的 生物标志物。 作为主要终点，我们将评估肿瘤数量。 尺寸 组胺水平，肿瘤浸润的数量和类型 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 测定 我们将比较西咪替丁与其他H2阻滞剂（雷尼替丁 和法莫替丁）和质子泵抑制剂奥美拉唑。 3. 向MIN小鼠施用两种候选化学预防剂的组合， 具体目标#1中确定的具有不同作用机制的药剂 和#2并评估肿瘤结果和相关生物标志物。 4. 向FAP患者施用候选化学预防剂， 随机、舒林酸对照、双盲、交叉试验， 通过视频内窥镜依次监测息肉数量。 我们还将 依次评估腺瘤中的息肉大小和适当的生物标志物， 结直肠粘膜

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.