PRIMARY CHEMOPREVENTION IN ADENOMATOUS POLYPOSIS COLI

家族性腺瘤性结肠息肉病（FAP）是一种常染色体显性遗传病， 由于APC种系改变引起的综合征（腺瘤性息肉病 大肠杆菌）基因最近发现的5号染色体上。 FAP介绍 通过形成数百个结肠直肠腺瘤性息肉 在儿童和年轻人中。几乎所有患有FAP的人都会 如果不进行预防性结肠切除术，则会发生结肠直肠癌。 我们 其他研究表明，舒林酸，一种前列腺素抑制剂， 抑制FAP患者中已形成的腺瘤性息肉。 我们的长期 目的是发现有效的化学预防疗法， FAP，代表一个模型，可以提供基本的见解 在其他高风险中腺瘤-癌序列的分子调控 癌症综合征和普通结直肠癌。 对高危患者进行症状前检测， 由于APC基因的生殖系突变而受到FAP的基因型影响， 现在结束吧 我们的假设是舒林酸作为一种化学预防剂 药物可以防止基因型中腺瘤的表型表达， 患有FAP的患者。 我们的具体目标是：l）给予基因型受影响的舒林酸 但表型未受影响的FAP患者， 安慰剂对照双盲试验 我们将评估 舒林酸的剂量和年轻人群的依从性 血浆舒林酸水平，并通过以下方法评价舒林酸的疗效： 连续监测息肉发育、息肉数量和大小， 通过视频内窥镜。 2)在扁平和息肉样病变中依次评估 结直肠粘膜鸟氨酸脱羧酶和S- 腺苷甲硫氨酸脱羧酶（多胺途径中的酶）， 上皮细胞增殖免疫组化法检测增殖细胞 核抗原和前列腺素水平，以确定 舒林酸效应

Familial adenomatous polyposis coli (FAP) is an autosomal dominant syndrome due to germline alteration of the APC (Adenomatous Polyposis Coli) gene recently discovered on chromosome 5. FAP presents phenotypically by formation of hundreds of colorectal adenomatous polyps in children and young adults. Virtually all individuals with FAP will develop colorectal cancer if prophylactic colectomy is not performed. We and others have shown that sulindac, a prostaglandin inhibitor, can suppress established adenomatous polyps in FAP patients. Our long term goal is to discover effective chemopreventive therapy for patients with FAP, representing a model which may provide basic insights into the molecular regulation of the adenoma-carcinoma sequence in other high-risk cancer syndromes and ordinary colorectal cancer. Presymptomatic testing of at-risk patients to determine those genotypically affected by FAP due to germline mutation of the APC gene can now be done. Our hypothesis is that sulindac used as a chemopreventive agent can prevent the phenotypic expression of adenomas in genotypically affected patients with FAP. Our specific aims are to: l) Administer sulindac to genotypically affected but phenotypically unaffected FAP patients in a randomized, long-term, placebo-controlled, double-blinded trial. We will assess the tolerability of sulindac and the compliance in a young aged population by measurement of plasma sulindac levels, and evaluate efficacy of sulindac by sequentially monitoring for polyp development, polyp number and size using by video endoscopy. 2) Sequentially assess in flat and polypoid colorectal mucosa the activity of ornithine decarboxylase and S- adenosylmethionine decarboxylase (enzymes in the polyamine pathway), epithelial proliferation by immunohistochemistry for proliferating cell nuclear antigen, and prostaglandin levels to determine mechanism(s) of sulindac effect.