MDC-1231 for cancer prevention

MDC-1231 用于预防癌症

• 批准号: 8547784
• 负责人: Basil Rigas
• 金额: $ 102.28万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547784
• 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.

描述（由申请人提供）：结肠癌的化学预防因药物效果较弱或副作用显着而受到阻碍。最近的研究表明，舒林酸与二氟甲基鸟氨酸 (DFMO) 的组合可以预防近 70% 的结肠癌（评估为结肠息肉复发）。然而，舒林酸具有频繁且显着的副作用，使其在癌症预防中的长期应用存在问题。我们的 I 期 STTR 评估了我们的舒林酸类化合物 MDC-1231（也称为磷酸舒林酸 (PS)）在预防结肠癌中的潜在作用。与舒林酸相比，PS 的效力和安全性更高，并与 DFMO 协同作用，预防结肠癌，有效率达 91%。我们的目标是与 DFMO 成功组合，用 PS 取代舒林酸，从而开发出一种更好的结肠癌预防方法。我们已经完成了第一阶段资助的所有目标。目前二期申请的目标是完成PS的临床前开发并提交FDA IND申请。我们提出了五个具体目标，其中一些目标将并行实现并相互影响。具体目标#1：完成代谢研究；对优化的 PS 口服制剂进行 PK/PD 和生物分布。具体目标#2：在 GMP 条件下扩大 PS 的合成规模。具体目标#3：开发 PS 口服制剂并确定其稳定性。具体目标#4：进行 PS 毒性研究；它们包括动物毒性和遗传毒性研究。具体目标#5：准备 IND 方案和包以供 FDA 提交。拟议的工作如果成功，将为人类结肠癌化学预防的现实策略做出巨大贡献。