POLYAMINE DEPLETION AND CHEMOPREVENTION OF COLON CANCER

这个项目是使用互动研究的三个提案之一 项目赠款机制，以确定多胺抑制剂是否 新陈代谢可以用于预防人类的结肠癌。这个 中期目标将是防止腺瘤复发 息肉，结直肠癌的替代品。《公约》的具体目标 目前的建议是：1)测量慢性低剂量的影响 二氟甲基鸟氨酸(DFMO)对直肠黏膜多胺水平的影响 2)测定小剂量DFMO对小鼠脑、肾组织的影响。 听力测量听力。在一项短期的IIa期试验中， 参与者接受了一个月的不同剂量的DFMO口服和 测定直肠粘膜活检组织中多胺合成的影响。 根据这些数据，我们设计了一个较长期(一年)的IIb阶段 试验中，四组各25名参与者将被随机分配到 接受口服安慰剂、DFMO(低剂量)、DFMO(中剂量)、 DFMO(大剂量)治疗1年。以下参数将是 连续测量：正规测听和直肠内多胺含量 粘膜活组织检查。生化指标和临床副作用将 也被监控。数据管理和分析将是彻底的和 很详细。这次试验的结果应该能让我们准确地 确定DFMO的剂量，以减少多胺含量并产生 几乎没有副作用。随后，将使用该剂量的DFMO 在未来的研究中：一项随机阶段的疾病试验 观察DFMO对减少结肠息肉复发的作用。

This project is one of three proposals that uses the Interactive Research Project Grant mechanism to determine if inhibitors of polyamine metabolism can be used to prevent colon cancer in humans. The intermediate-term objective will be to prevent recurrence of adenomatous polyps, a surrogate for colo-rectal cancer. The specific aims of the current proposal are: 1) to measure the effects of chronic low dose difluoromethylornithine (DFMO) on polyamine levels in rectal mucosal tissues, and 2) to determine the effect of low dose DFMO on audiometric-measured hearing. In a short-term phase IIa trial, participants have received different doses of oral DFMO for one month and the effect on polyamine synthesis in rectal mucosal biopsies measured. Based on this data we have designed a longer term (one year) phase IIb trial in which four groups of 25 participants each will be randomized to receive either oral placebo, DFMO (low dose), DFMO (intermediate dose), and DFMO (high dose) for one year. The following parameters will be measured serially: formal audiometry, and polyamine content in rectal mucosal biopsies. Biochemical parameters and clinical side effects will also be monitored. Data management and analysis will be thorough and detailed. The results from this trial should allow us to accurately determine the dose of DFMO that will reduce polyamine content and produce little to no side effects. Subsequently, this dose of DFMO would be used in a future investigation: a randomized phase Ill trial in which the effect of DFMO on reducing colon polyp recurrence would be measured.