EFFECTS OF URSODEOXYCHOLIC ACID ON ADENOMATOUS POLYP RECURRENCE

本研究项目的总体目标是评估 熊去氧胆酸（UDCA）治疗可降低发病率， 结直肠癌的死亡率是第二大原因， 1993年美国有53，000人死于癌症。 腺瘤性结肠息肉是公认的结直肠癌的前兆 最近的癌症预防工作集中在他们的早期 通过结肠镜检查检测和去除。然而，这种方法是 由于结肠镜检查的费用和风险， 以及结肠腺瘤容易复发的事实。最近的描述 分子遗传变化的特征， 腺瘤转化为癌的可能性提高了基因分析的可能性， 外周血白细胞可以识别风险增加的人， 结肠癌的未来发展被如此确认的个人， 由于大量患者人群具有先前的散发性 结肠直肠腺瘤，可能会受益于治疗 干预，抑制内源性和 结肠粘膜上的环境癌症促进剂。过去50 多年来，各种流行病学和实验研究 强烈支持粪便次级胆汁酸的重要作用， 特别是脱氧胆酸（DCA），在促进结肠癌中的作用。UDCA是 一种三级胆汁酸，通常在人胆汁中少量存在。 与DCA相比，UDCA对结肠粘膜无毒性， 在实验动物中促进结肠癌。恰恰相反， 强烈的保护。这项提案的目标是确定在人类中， UDCA治疗是否会抑制结直肠腺瘤复发 和/或不利特征的发展（例如，遗传 改变和/或DNA非整倍体）与癌症风险增加相关 任何复发性腺瘤。这项研究是一项前瞻性的， 随机双盲III期试验，其中1200例患者 切除的结直肠腺瘤将被分配治疗3年 UDCA（8-10 mg/kg/天）或安慰剂。尺寸，类型，数量，位置， 在排位赛中切除的结肠腺瘤的DNA倍体状态 将结肠镜检查结果与基线粪便和血浆胆汁酸进行比较。 将对任何相同的参数（不包括DNA倍性）进行评价。 UDCA治疗完成时通过结肠镜检查发现并切除息肉。 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（例如，PCNA）和表达 将评估蛋白激酶C同种型和/或酶活性 在通过直肠粘膜活检获得的25%亚组的正常平坦粘膜中， 的受试者，并将结果与 血浆和粪便。UDCA副作用和治疗依从性也将 被评价。本研究有足够的把握度确定UDCA是否 很可能是一种有效的化学预防剂， 增加结肠直肠腺瘤复发的风险， 有利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.