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MDC-1231 for cancer prevention

MDC-1231 用于预防癌症

基本信息

批准号：
7999694
负责人：
Basil Rigas
金额：
$ 18.75万
依托单位：
MEDICON, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7999694
关键词：
Accounting Acetylation Adverse effects Anti-Inflammatory Agents Anti-inflammatory Cancer Cell Growth Cancer Control Cells Cessation of life Chemoprevention Chemopreventive Agent Clinical Trials Colon Carcinoma Colorectal Cancer DL-alpha-Difluoromethylornithine Development Drug Kinetics Drug toxicity Enzymes Exanthema Figs - dietary Hepatic Human Individual Kidney Life Malignant Neoplasms Molecular Target Nude Mice Ornithine Decarboxylase Patients Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Plasma Polyamines Pre-Clinical Model Prevention Pruritus Public Health Recurrence Safety Seminal Sulindac Time Toxic effect Western World Work Xenograft procedure adenoma cancer prevention chemotherapy drug efficacy drug metabolism gastrointestinal metabolic abnormality assessment novel pre-clinical preclinical evaluation preclinical study prevent public health relevance

项目摘要

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.

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安全有效的药物的开发。 NSAIDs 可以预防结直肠癌，但有两个主要局限性，妨碍其大规模应用来预防结直肠癌：a) 显着的副作用，在美国每年导致超过 15,000 人死亡； b) 功效有限，充其量也低于 50%。预防结肠癌的一项重大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并从细胞输出，而 DFMO 抑制鸟氨酸脱羧酶，该酶催化多胺合成中的限速步骤。最终结果是降低多胺水平，从而抑制癌细胞的生长。我们合成了 MDC-1231，这是一种新型化合物，a) 与 DFMO 联合使用时，在临床前模型中几乎可以完全预防结肠癌，b) 看起来很安全。我们的假设是，MDC-1231 是一种安全的，与 DFMO 联合使用时，是一种高效的结肠癌化学预防剂。为了评估这一假设，我们提出以下具体目标：1）确定MDC-1231加DFMO对裸鼠人结肠癌异种移植物的化学预防效果； 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 的临床前开发并最终进入 I 期临床试验铺平道路。公共卫生相关性：抗炎药舒林酸与另一种化合物 (DFMO) 结合可预防结肠癌。然而，舒林酸具有显着的副作用，尤其是长时间服用时。 MDC-1123是一种新型舒林酸类药物，在临床前研究中显示在预防结肠癌方面更安全且非常有效。这项工作对公共卫生的影响将是巨大的，因为它将有助于制定有效的结肠癌控制策略。