FOLATE--EFFECTS ON INTERMEDIARY MARKERS OF COLON CANCER

本提案的主要目标是：1)初步确认 人类普遍存在DNA低甲基化现象的观察 患有结直肠腺瘤的个人；2)确定是否每天 补充药理剂量的叶酸可能会减弱或 逆转DNA低甲基化或更传统地接受的 结直肠癌的中间标记物、增殖 直肠乙状结肠黏膜；3)确定这种补充是否可以 提供无明显副作用的产品；以及4) 检查补充叶酸是否对 这些中间标记可持续长达一年。 停用维生素。 结直肠癌是世界上第二大癌症死亡原因。 在美国和大多数发达国家。尽管不同凡响 在过去的五十年里，治疗方式的进步，年龄- 调整后的癌症死亡率基本保持不变。 结肠镜检查高危人群 疾病可能会降低死亡率，但对 社会。此外，此方法不会移除基础的 倾向于结肠癌的发生。寻求一种有效的和 因此，安全的化学预防药物是有保证的。流行病学研究 而动物实验表明，饮食之间存在相反的关系 维生素叶酸的摄入与结直肠癌的发病风险 不典型增生和癌症。此外，初步证据显示， 海港结肠腺瘤提示DNA低甲基化，a 在结直肠肿瘤中普遍观察到的生化现象 它可能在癌症的发生中起到致病作用 作为一种广泛存在于大肠粘膜中的系统性病变， 补充药理剂量的叶酸可能会逆转这种情况 异常现象。 该研究设计为前瞻性、双盲、安慰剂对照、 多中心试验。这项工作将在以下机构的全力配合下进行 东方协作肿瘤学小组(ECOG)，一个历史悠久的大型组织 由医疗中心组成的联盟，在 成功开展大型临床试验。受试者最近 曾在结肠镜下切除腺瘤的患者将随机接受 或者5毫克。每日服用叶酸片剂或服用安慰剂，为期一年。重复 在6个月、1年和2年进行结肠镜检查以监测 中间标记。粘膜增殖和DNA的改变 叶酸干预后发生的低甲基化将是 比较，提供了一种确定DNA测量是否 甲基化反应与更多常规接受的反应相似 中间标记。这次试验的结果将被用来确定 是否需要进行更大规模和更长时间的第三阶段试验，其中 终点将由腺瘤和癌症发生组成。

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.