FOLATE--EFFECTS ON INTERMEDIARY MARKERS OF COLON CANCER

本提案的主要目标是：1）确认初步 关于DNA低甲基化的广泛性质的观察， 患有结直肠腺瘤的人; 2）确定是否每天 补充药理学剂量的叶酸可以减弱或 逆转DNA低甲基化或更普遍接受的 结直肠癌的中间标志物， 直肠乙状结肠粘膜; 3）确定这种补充是否可以 没有显著的副作用发生率;以及4） 检查叶酸补充剂是否对 这些中间标记物在感染后持续长达一年， 停止服用维生素。 结肠直肠癌是癌症死亡的第二大常见原因， 美国和大多数发达国家。 尽管有着非凡的 在过去的五十年里，治疗方式的进步，年龄- 这种癌症的调整后死亡率基本保持不变。 结肠镜筛查的个人谁是在增加的风险， 疾病可以降低死亡率，但要付出巨大的经济代价， 社会此外，这种方法并没有消除潜在的 倾向于结肠癌发生。寻求有效的， 因此，安全的化学预防剂是必要的。流行病学研究 动物实验表明，饮食与 维生素叶酸的摄入量和患结肠直肠癌的风险 发育不良和癌症。此外，初步证据表明， 港湾结直肠腺瘤表明DNA低甲基化， 在结直肠肿瘤中一致观察到的生化现象 并可能在致癌作用中起致病作用， 全身性和结肠直肠粘膜的广泛病变， 补充药理学剂量的叶酸可以逆转这些 异常 研究设计为前瞻性、双盲、安慰剂对照， 多中心试验它将在联合国秘书长的充分合作下进行。 东部肿瘤协作组（ECOG）是一个大型的、完善的 医疗中心联盟，具有良好的记录， 成功开展大型临床试验。受试者最近 将接受结肠镜腺瘤切除术的患者随机分配至 5 mg。每天服用叶酸片或安慰剂一年。重复 将在6个月、1年和2年时进行结肠镜检查， 中间标记。粘膜增殖和DNA的改变 响应叶酸干预而发生低甲基化将 比较，提供了一种确定DNA测量是否 甲基化与在更常规接受的 中间标记。这项试验的结果将用于确定 是否有必要进行更大更长的III期试验， 终点将包括腺瘤和癌症的发生。

The major goals of this proposal are 1) to confirm preliminary observations regarding the widespread nature of DNA hypomethylation in individuals who have colorectal adenomas; 2) to determine whether daily supplementation with pharmacologic doses of folic acid may attenuate or reverse either DNA hypomethylation or a more conventionally-accepted intermediary marker of colorectal cancer, the proliferation of the rectosigmoid mucosa; 3) to determine whether such supplementation can be provided without a significant incidence of side effects; and 4) to examine whether any beneficial effects of folic acid supplementation on these intermediary markers persist for up to one year after discontinuation of the vitamin. Colorectal cancer is the second most common cause of cancer death in the United States and in most of the developed world. Despite the remarkable advances in therapeutic modalities over the past five decades, the age- adjusted death rate from this cancer has remained essentially unchanged. Colonoscopic screening of individuals who are at enhanced risk of the disease may reduce mortality, but at an extraordinary financial cost to society. Furthermore, this approach does not remove the underlying disposition towards colonic carcinogenesis. A search for an effective and safe chemopreventive agent is therefore warranted. Epidemiologic studies and animal experiments indicate an inverse relationship between dietary intake of the vitamin folate and the risk of developing colorectal dysplasia and cancer. Furthermore, preliminary evidence in individuals who harbor colorectal adenomas indicates that DNA hypomethylation, a biochemical phenomenon which is uniformly observed in colorectal neoplasms and which may play a causative role in carcinogenesis, is present systemically and as a widespread lesion in the colorectal mucosa, and that supplementation with pharmacologic doses of folic acid may reverse these abnormalities. The study design is a prospective, double-blind, placebo-controlled, multi-center trial. It will be conducted with the full cooperation of the Eastern Collaborative Oncology Group (ECOG), a large and well-established consortium of medical centers that has an excellent record for the successful conduct of large clinical trials. Subjects who have recently had colonoscopic resection of adenomas will be randomized to receive either 5 mg. tablets of folic acid daily or a placebo for one year. Repeat colonoscopy at 6 months, 1 year, and 2 years will be performed to monitor the intermediary markers. Alterations in mucosal proliferation and DNA hypomethylation which occur in response to folate intervention will be compared, providing a means of determining whether the measurement of DNA methylation parallels the response seen in more conventionally-accepted intermediary markers. The results of this trial will be used to determine whether a larger and longer Phase III trial is warranted, in which the endpoints will consist of adenoma and cancer occurrence.