POLYAMINE DEPLETION AND CHEMOPREVENTION OF COLON CANCER

多胺消耗和结肠癌的化学预防

• 批准号: 2099665
• 负责人: FRANK L. MEYSKENS
• 金额: $ 10.59万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2099665
• 关键词: adenomatous polyps; antimetabolites; audiometry; cancer prevention; chemoprevention; clinical trials; colorectal neoplasms; difluoromethylornithine; dosage; drug adverse effect; drug screening /evaluation; hearing; human subject; mucosa; neoplasm /cancer pharmacology; ototoxin; polyamines; preneoplastic state; adenomatous polyps; antimetabolites; audiometry; cancer prevention; chemoprevention; clinical trials; colorectal neoplasms; difluoromethylornithine; dosage; drug adverse effect; drug screening /evaluation; hearing; human subject; mucosa; neoplasm /cancer pharmacology; ototoxin; polyamines; preneoplastic state

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.

该项目是使用互动研究的三个建议之一 项目授予机制以确定多胺抑制剂是否 代谢可用于预防人类中的结肠癌。 这 中期目标将是防止腺瘤的复发 息肉，是神经直肠癌的替代物。 特定目标 当前建议是：1）测量慢性低剂量的影响 直肠粘膜中多胺水平的差异甲基氨酸（DFMO） 组织，2）确定低剂量DFMO对 听力测量听力。 在短期IIA阶段试验中， 参与者已经收到不同剂量的口服DFMO一个月， 测量直肠粘膜活检中多胺合成的影响。 基于这些数据，我们设计了一个长期（一年）IIB 试验，其中四组25名参与者将被随机分配给 接受口服安慰剂，DFMO（低剂量），DFMO（中剂量）， 和DFMO（高剂量）一年。 以下参数将是 串行测量：正式的听力测定法和直肠多胺含量 粘膜活检。 生化参数和临床副作用将 也可以监视。 数据管理和分析将是彻底的，并且 详细的。该试验的结果应使我们能够准确 确定DFMO的剂量，该剂量将减少多胺含量并产生 几乎没有副作用。 随后，将使用这种DFMO剂量 在以后的调查中：一项随机阶段疾病试验 将测量DFMO对减少结肠息肉复发的影响。