MDC-1231 for cancer prevention

描述（由申请人提供）：强有力的证据支持化学预防有可能成为结直肠癌控制的主要组成部分的观点。癌症的预防在很大程度上取决于开发安全有效的药物。NSAID预防结肠直肠癌，但有两个主要的限制，这妨碍了它们大规模应用于预防结肠直肠癌：a）显著的副作用，在美国每年造成> 15，000例死亡;和B）有限的功效，其最多低于50%。预防结肠癌的一个重要进展是联合使用舒林酸和二氟甲基鸟氨酸（DFMO）;舒林酸刺激多胺乙酰化和从细胞中输出，DFMO抑制酶鸟氨酸脱羧酶，该酶催化多胺合成中的限速步骤。最终结果是多胺水平降低，导致癌细胞生长受到抑制。我们已经合成了MDC-1231，一种新型化合物，a）当与DFMO组合时，在临床前模型中几乎完全预防结肠癌，并且B）看起来是安全的。我们的假设是，MDC-1231是一种安全的，当与DFMO联合使用时，对结肠癌是一种高效的化学预防剂。为了评估这一假设，我们提出了以下具体目标：1）确定MDC-1231联合DFMO在裸鼠人结肠癌异种移植物中的化学预防功效; 2）进行MDC-1231联合DFMO的毒性研究; 3）研究MDC-1231的代谢、药代动力学和药效学。这些目标将评估对MDC-1231开发至关重要的参数。拟议研究的结果将为完成MDC-1231的临床前开发铺平道路，最终导致I期临床试验。 公共卫生相关性：抗炎药舒林酸与另一种化合物（DFMO）联合使用可预防结肠癌。然而，舒林酸具有显著的副作用，特别是当长时间给予时。MDC-1123是一种新型舒林酸类药物，在临床前研究中似乎更安全，在预防结肠癌方面非常有效。这项工作将对公共卫生产生重大影响，因为它将有助于制定一项控制结肠癌的有效战略。

DESCRIPTION (provided by applicant): Strong evidence supports the notion that chemoprevention has the potential to be a major component of colorectal cancer control. The prevention of cancer depends heavily on the development of safe and effective agents. NSAIDs prevent colorectal cancer but have two major limitations that preclude their large-scale application to prevent colorectal cancer: a) significant side effects, accounting per year for >15,000 deaths in the US; and b) limited efficacy, which, at best, is below 50%. A significant development in the prevention of colon cancer is the combined use of sulindac and difluoromethylornithine (DFMO); sulindac stimulates polyamine acetylation and export from the cell and DFMO inhibits the enzyme ornithine decarboxylase, which catalyzes the rate-limiting step in polyamine synthesis. The end result is reduced polyamine levels leading to suppressed growth of cancer cells. We have synthesized MDC-1231, a novel compound that a) when combined with DFMO prevents nearly completely colon cancer in preclinical models, and b) appears safe. Our hypothesis is that MDC-1231 is a safe and, when combined with DFMO, highly effective chemopreventive agent against colon cancer. To evaluate this hypothesis, we propose the following specific aims: 1) Determine the chemoprevention efficacy of MDC-1231 plus DFMO in human colon cancer xenografts in nude mice; 2) Perform toxicity studies of MDC-1231 combined with DFMO; and 3) Study the metabolism, pharmacokinetics and pharmacodynamics of MDC-1231. These aims will assess parameters that are essential to the development of MDC-1231. The results of the proposed studies will pave the way towards the completion of the preclinical development of MDC-1231 ultimately leading to a phase I clinical trial. PUBLIC HEALTH RELEVANCE: The anti-inflammatory drug sulindac combined with another compound (DFMO) prevents colon cancer. Sulindac, however, has significant side effects especially when given for prolonged periods of time. MDC-1123 is a novel sulindac-like drug that in preclinical studies appears safer and very effective in the prevention of colon cancer. The impact of this work on public health will be significant, as it will contribute to the development of an effective strategy for the control of colon cancer.