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）：有力的证据支持这样的观念：化学预防有可能成为结直肠癌控制的主要组成部分。癌症的预防在很大程度上取决于安全有效的药物的发展。 NSAIDS预防结直肠癌，但具有两个主要局限性，排除了其大规模应用以预防大肠癌：a）在美国，每年的副作用，每年占15,000人死亡； b）有限的疗效，充其量至少低于50％。预防结肠癌的重大发展是苏氏菌和二氟甲基氨酸（DFMO）的综合使用。 Sulindac刺激多胺乙酰化并从细胞中导出，DFMO抑制鸟氨酸脱羧酶，从而催化多胺合成中的速率限制步骤。最终结果是多胺水平降低，导致癌细胞的生长受到抑制。我们已经合成了MDC-1231，这是一种新型化合物。我们的假设是，MDC-1231是一种安全，并且与DFMO结合使用，针对结肠癌的高效化学预防剂。为了评估这一假设，我们提出了以下具体目的：1）确定MDC-1231加上DFMO在裸鼠中人类结肠癌异种移植物中的化学预防疗效； 2）对MDC-1231进行毒性研究与DFMO结合； 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发展至关重要的参数。拟议的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Sulindac与另一种化合物（DFMO）相结合可防止结肠癌。然而，苏琳克具有显着的副作用，尤其是在长时间的时间内给予的副作用。 MDC-1123是一种新型的类似苏氏糖的药物，在临床前研究中看起来更安全，非常有效地预防结肠癌。这项工作对公共卫生的影响将非常重要，因为这将有助于制定控制结肠癌的有效策略。