POLYAMINE DEPLETION AND CHEMOPREVENTION OF COLON CANCER

该项目是使用互动研究的三个提案之一 项目资助机制，以确定是否多胺抑制剂 代谢可以用于预防人类结肠癌。 的 中期目标将是防止腺瘤复发， 息肉，结肠直肠癌的替代品。 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）对直肠粘膜多胺水平的影响 组织，和2）以确定低剂量DFMO对 听力测定的听力。 在短期IIa期试验中， 参与者接受不同剂量的口服DFMO一个月， 测量直肠粘膜活检对多胺合成的影响。 基于这些数据，我们设计了一个更长期（一年）的IIb期研究 在一项试验中，四组25名参与者将被随机分配到 接受口服安慰剂、DFMO（低剂量）、DFMO（中等剂量）， DFMO（高剂量）治疗一年。 以下参数 连续测量：正式测听和直肠多胺含量 粘膜活检。 生化参数和临床副作用将 也被监控。 数据管理和分析将是彻底的， 详细的这次试验的结果应该能让我们准确地 确定DFMO的剂量，这将减少多胺含量，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III期试验， 将测量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.