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 APC(腺瘤性息肉病)胚系改变引起的综合征 最近在5号染色体上发现)基因。FAP呈现 数百例结直肠腺瘤性息肉的表型 在儿童和年轻人身上。几乎所有患有FAP的人都会 如果不进行预防性结肠切除术，就会患上结直肠癌。我们 另一些研究表明，前列腺素抑制剂舒林酸可以 抑制FAP患者已建立的腺瘤性息肉。我们的长期计划 目标是找到有效的化学预防方法来治疗慢性前列腺癌患者 FAP，代表一个模型，它可以提供对 其他高危人群腺瘤-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测试以确定 由于APC基因的种系突变而受到FAP的基因影响 现在就去做吧。我们的假设是舒林酸被用作化学预防 药物可抑制遗传性腺瘤的表型表达 受FAP影响的患者。 我们的具体目标是：L)给药舒林酸治疗遗传性疾病 但表型未受影响的FAP患者随机、长期、 安慰剂对照双盲试验。我们将评估其耐受性 舒林酸在青年人群中的依从性测量 血浆舒林酸水平，并评价舒林酸的疗效 连续监测息肉的发展、息肉数量和大小 通过视频内窥镜检查。2)平坦型和多角型顺序评估 大肠粘膜鸟氨酸脱羧酶活性与S 腺苷甲硫氨酸脱羧酶(多胺途径中的酶)， 增殖细胞的免疫组织化学方法检测上皮细胞增殖 核抗原与前列腺素水平关系的机制探讨(S) 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.