MDC-1231 for cancer prevention

MDC-1231 用于预防癌症

• 批准号: 8257195
• 负责人: Basil Rigas
• 金额: $ 73.95万
• 依托单位: MEDICON, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257195
• 关键词: Abdominal Pain; Address; Adverse effects; Affect; Animals; Aspirin; Biodistribution; Cancer Etiology; Cardiotoxicity; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Colon Carcinoma; Colonic Polyps; DL-alpha-Difluoromethylornithine; Development; Dizziness; Dose; Drowsiness; Drug Formulations; Drug Kinetics; Exanthema; Fright; Goals; Grant; HT29 Cells; Headache; Hemorrhage; Hepatotoxicity; Histologic; Human; Hydrolysis; Intestinal Mucosa; Liver Microsomes; Metabolism; Modeling; Molecular Target; Mus; Nausea; Nervousness; New Agents; Oral; Organ; Oxidation-Reduction; PTGS2 gene; Pancreas; Paper; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Placebos; Prevention; Protocols documentation; Pruritus; Rattus; Reaction; Recurrence; Renal function; Role; Safety; Series; Serum; Small Business Technology Transfer Research; Sulindac; Testing; Toxic effect; Ulcer; Work; Xenograft procedure; absorption; cancer chemoprevention; cancer prevention; gastrointestinal; genotoxicity; inhibitor/antagonist; liver function; meetings; novel; pre-clinical; preclinical evaluation; prevent; safety study; scale up; tumor growth

DESCRIPTION (provided by applicant): The chemoprevention of colon cancer has been hampered by either weak agents or significant side effects. It was recently shown that the combination of sulindac with difluoromethylornithine (DFMO) prevents nearly 70% of colon cancer, assessed as colon polyp recurrence. Sulindac, however, has frequent and significant side-effects that make its long-term application to cancer prevention problematic. Our phase I STTR assessed the potential role of our sulindac-like compound MDC-1231, also known as phosphosulindac (PS), in colon cancer prevention. PS has increased potency and safety compared to sulindac and acts synergistically with DFMO to prevent colon cancer with an efficacy of 91%. Our goal is to replace sulindac with PS in the successful combination with DFMO in order to develop a superior approach to colon cancer prevention. We have accomplished all the goals of the phase I grant. The goal of the present phase II application is to complete the preclinical development of PS and submit an FDA IND application. We propose five specific aims, some of them will be pursued in parallel and influence each other. Specific Aim #1: Complete the studies on the metabolism; perform PK/PD and biodistribution of the optimized oral formulation of PS. Specific Aim #2: Scale up the synthesis of PS under GMP conditions. Specific Aim #3: Develop an oral formulation of PS and determine its stability. Specific Aim #4: Perform toxicity studies of PS; they include animal toxicity and genotoxicity studies. Specific Aim #5: Prepare an IND protocol and package for FDA submission. The proposed work, if successful, will contribute greatly towards a realistic strategy for human colon cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Colon cancer is a major cause of cancer deaths in the US and worldwide. The prevention of colon cancer using pharmacological agents is now a realistic possibility, but new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, which is potentially a highly effective and safe chemopreventive agent. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.

描述（由申请人提供）：结肠癌的化学预防受到弱药或重大副作用的阻碍。最近表明，苏氏酸与二氟甲基氨酸（DFMO）的结合可防止近70％的结肠癌，被评估为结肠息肉复发。然而，苏琳克具有频繁且重要的副作用，使其长期用于预防癌症的问题。我们的I阶段STTR评估了我们的Sulindac样化合物MDC-1231（也称为Phosphoslindac（PS））在结肠癌预防中的潜在作用。与苏琳克相比，PS具有提高的效力和安全性，并与DFMO协同起作用，以预防91％的疗效结肠癌。我们的目标是在成功结合DFMO中将Sulindac用PS代替，以开发出卓越的结肠癌预防方法。我们已经实现了我授予的所有目标。本II阶段应用程序的目的是完成PS的临床前开发并提交FDA IND应用程序。我们提出了五个具体目标，其中一些将与之并联并相互影响。特定目的＃1：完成有关新陈代谢的研究；执行PK/PD和PS优化口服公式的生物分布。特定目的＃2：在GMP条件下扩大PS的合成。特定目的＃3：开发PS的口服公式并确定其稳定性。特定目的＃4：对PS进行毒性研究；它们包括动物毒性和遗传毒性研究。特定目标＃5：为FDA提交准备IND协议和软件包。拟议的工作，如果成功的话，将为人类结肠癌化学预防的现实策略做出很大贡献。 公共卫生相关性：结肠癌是美国和全球癌症死亡的主要原因。现在，使用药理学剂预防结肠癌是现实的可能性，但迫切需要新的药物。我们提议开发一种新型化合物磷酸硫酸盐，该化合物可能是一种高效且安全的化学预防剂。预期的结果将铺平磷酸化 - 苏列达克的临床前评估，这是在其在人类中进行测试之前所需的步骤。