MDC-1231 for cancer prevention

描述(由申请人提供)：结肠癌的化学预防一直受到弱药剂或显著副作用的阻碍。最近有研究表明，舒林酸和二氟甲基鸟氨酸(DFMO)的联合使用可以预防近70%的结肠癌(被评估为结肠息肉复发)。然而，舒林酸有频繁而显著的副作用，这使得它在癌症预防中的长期应用成为问题。我们的第一阶段STTR评估了我们的舒林酸类化合物MDC-1231，也被称为磷酸(PS)，在结肠癌预防中的潜在作用。与舒林酸相比，PS具有更高的效力和安全性，并与DFMO协同作用预防结肠癌，有效率为91%。我们的目标是在与DFMO的成功结合中用PS取代舒林酸，以开发一种更好的结肠癌预防方法。我们已经完成了第一阶段授予的所有目标。目前第二阶段申请的目标是完成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推进，并相互影响。具体目标#1：完成PS的代谢研究；进行PS优化口服制剂的PK/PD和生物分布。具体目标#2：在GMP条件下放大合成PS。具体目标#3：研制PS的口服制剂并测定其稳定性。具体目标#4：进行PS的毒性研究；包括动物毒性和遗传毒性研究。具体目标5：为FDA提交的IND方案和包做好准备。这项拟议的工作，如果成功，将极大地促进人类结肠癌化学预防的现实战略。

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.