EFFECTS OF URSODEOXYCHOLIC ACID ON ADENOMATOUS POLYP RECURRENCE

这项研究计划的总体目标是评估 熊去氧胆酸(UDCA)治疗可降低发病率和 结直肠癌死亡率是人类死亡的第二大原因 1993年，美国的癌症死亡人数为5.3万人。 腺瘤性结肠息肉是公认的结直肠癌的先兆 最近在癌症预防方面的努力集中在它们的早期 结肠镜检查和切除。然而，这种方法是 有问题，因为结肠镜检查的费用和风险 结肠腺瘤往往会复发。最近的描述 分子遗传变化的特征是从一个 腺瘤到癌增加了基因分析的可能性 外周血白细胞可识别高危人群 结肠癌的未来发展。如此识别的个人，以及 因为大量的患者群体有先前的零星病史 结直肠腺瘤，可能会从治疗中受益 抑制内源性和外源性因素影响的干预 结肠粘膜上的环境致癌促进剂。在过去50年里 多年来，各种流行病学和实验研究已经 强烈支持粪便次级胆汁酸的重要作用， 尤其是脱氧胆酸(DCA)，在促进结肠癌方面。UDCA是 一种三级胆汁酸，通常以少量存在于人体胆汁中。 与DCA相比，UDCA对结肠粘膜没有毒性，也没有 在实验动物中促进结肠癌。恰恰相反，它是 具有很强的保护性。这项提议的目标是在人类身上确定 UDCA治疗是否会抑制结直肠腺瘤的复发 和/或不良特征的发展(例如遗传 改变和/或DNA非整倍体)与癌症风险增加相关 有无复发的腺瘤。拟议的研究是一项前瞻性的研究， 1200名患者参加的随机双盲Ill试验 切除的结直肠腺瘤将被分配治疗3年 使用UDCA(8-10毫克/公斤/天)或安慰剂。大小、类型、数量、位置、 结肠腺瘤切除后的DNA倍体状态 结肠镜检查将与基线粪便和血浆胆汁酸进行比较。 相同的参数(不包括DNA倍体)将被评估 UDCA治疗结束时，结肠镜检查发现并摘除息肉。 UDCA对其他替代终点生物标志物的影响，包括 结肠上皮细胞增殖(如增殖细胞核抗原)及其表达 将对蛋白激酶C亚型和/或酶活性进行评估 在25%的直肠粘膜活检获得的正常扁平粘膜中 将结果与胆汁酸浓度进行比较 血浆和大便。UDCA副作用和治疗依从性也将 被评估。这项研究有足够的力量来确定UDCA是否 可能是一种有效的化学预防药物，适用于以下人群 结直肠腺瘤复发的风险增加以及是否 有益地影响结肠癌风险的替代终点生物标志物。

The overall objective of this research program is to evaluate whether treatment with ursodeoxycholic acid (UDCA) can reduce the incidence and mortality of colorectal cancer which is the second leading cause of cancer death in the United States with 53,000 fatalities in 1993. Adenomatous colon polyps are a recognized precursor of colorectal cancer and recent efforts at cancer prevention have focused on their early detection and removal by colonoscopy. However this approach is problematic, owing to the expense and risk associated with colonoscopy and the fact that colon adenomas tend to recur. The recent description of molecular genetic changes that characterize progression from an adenoma to carcinoma raises the possibility that genetic analysis of peripheral blood leukocytes may identify persons at increased risk for future development of colon cancer. Individuals so identified, as well as the large patient population with a history of a prior sporadic colorectal adenoma, presumably would benefit from a treatment intervention which suppresses the effects of endogenous and environmental cancer promoters on the colonic mucosa. Over the past 50 years, a variety of epidemiological and experimental studies have strongly supported an important role for fecal secondary bile acids, especially deoxycholic acid (DCA), in promoting colon cancer. UDCA is a tertiary bile acid normally present in small amounts in human bile. In contrast to DCA, UDCA is not toxic to colonic mucosa and does not promote colon cancer in experimental animals. To the contrary, it is strongly protective. The goal of this proposal is to determine in humans whether UDCA treatment will suppress recurrence of colorectal adenomas and/or the development of adverse characteristics (e.g.. genetic alterations and/or DNA aneuploidy) associated with increased cancer risk in any recurrent adenomas. The proposed study is a prospective, randomized double-blind Phase Ill trial in which 1200 patients with resected colorectal adenomas will be assigned to treatment for 3 years with UDCA (8-10 mg/kg/day) or placebo. The size, type, number, location, and DNA ploidy status in colon adenomas removed at the qualifying colonoscopy will be compared with baseline fecal and plasma bile acids. The same parameters (excluding DNA ploidy) will be evaluated for any polyps found and removed by colonoscopy at completion of UDCA treatment. The effects of UDCA on other surrogate endpoint biomarkers, including colonic epithelial cell proliferation (e.g., PCNA) and the expression of protein kinase C isotypes and/or enzyme activity will be evaluated in normal flat mucosa obtained by rectal mucosal biopsy in a 25% subset of subjects and the results compared with bile acid concentrations in plasma and stool. UDCA side effects and treatment compliance will also be evaluated. The study has sufficient power to determine if UDCA is likely to be an effective chemopreventive agent for use in persons at increased risk for colorectal adenoma recurrence and whether it beneficially effects surrogate endpoint biomarkers of colon cancer risk.