Safer Approaches to CRC Chemoprevention

更安全的 CRC 化学预防方法

基本信息

批准号：
10063852
负责人：
Chinthalapally V. Rao
金额：
$ 38.98万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063852
关键词：
Adoptive Transfer American Arachidonate 5-Lipoxygenase Arachidonic Acids Arterial Fatty Streak Aspirin Atherosclerosis Azoxymethane Biological Assay Biological Models Bone Marrow C57BL/6 Mouse Cancer Etiology Cancer Model Cardiovascular system Chemopreventive Agent Chronic Clinical Clinical Trials Colon Adenocarcinoma Colon Carcinoma Colonic Neoplasms Colorectal Cancer Coxibs Data Development Diagnosis Dinoprostone Dose Early Intervention Eicosanoids Enzyme Kinetics Epidemiology Epoprostenol Exposure to Female Health High Fat Diet Inbred F344 Rats Individual Laboratories Lipoxygenase Inhibitors Modification Mus Non-Steroidal Anti-Inflammatory Agents Outcome Outcomes Research Patients Pharmaceutical Preparations Pharmacodynamics Pre-Clinical Model Prevention Preventive Property Prostaglandin Inhibition Prostaglandin-Endoperoxide Synthase Rattus Research Research Design Risk Risk Reduction Role Safety Serum Source Testing Thrombosis Tissue Sample Tissues Toxic effect atorvastatin base cancer chemoprevention cancer risk cancer therapy cardiovascular risk factor celecoxib colon cancer prevention colon cancer risk colorectal cancer prevention colorectal cancer risk colorectal cancer treatment combinatorial cyclooxygenase 1 cyclooxygenase 2 effective therapy efficacy study experimental study gastrointestinal heart function high risk improved in vivo inhibitor/antagonist macrophage male mortality mouse PGE synthase 1 novel novel therapeutics prevent response side effect thrombotic tissue biomarkers transcriptomics tumor tumor growth tumorigenic

项目摘要

Project Summary The major purpose of this proposed research is to develop mechanistically based, effective, and safer agents for colorectal cancer (CRC) chemoprevention. Every year, about 150,000 Americans are diagnosed with colorectal cancer (CRC), the second leading cause of cancer-related mortality in the US. About 1.35 million new CRC cases are diagnosed worldwide, highlighting that CRC is a major health problem. Evidence from our group and others suggests that NSAIDs and select COX-2 inhibitors show significant inhibitory effects in preclinical models and patients with CRC, but these inhibitors are also associated with gastrointestinal (GI) toxicity and cardiovascular (CV) risk. Reasons for these risks include increased 5-LOX metabolites and reduced PGI2 synthesis. Thus, selectively targeting microsomal PG Synthase-1 (mPGES-1) and 5-LOX would block the protumorigenic PGE2/prothrombotic LTs, but spare the PGI2. This approach is ideal for developing efficient and safer CRC chemopreventive agents. Toward this end, through high-throughput and enzyme kinetics assays and short- term in vivo efficacy studies, we have discovered a novel dual mPGES-1 /5-LOX inhibitor, CDPDPA. In this proposal, we seek to further develop CDPDPA for CRC chemoprevention. We have designed the research strategies to assess the pharmaco-dynamic dose-response efficacy, understand the role of mPGES-1/5- LOX, improve efficacy and safety through combinatorial approaches, and evaluate CV risk, if any, of CDPDPA compared with COX-2 inhibitor. We have assembled a team with expertise in CRC chemoprevention and cardivascular research to undertake following aims. 1). Determine whether targeting both mPGES-1 and 5-LOX with CDPDPA is efficacious in AOM-induced rat colon adenocarcinoma treatment; 2) Determine the source and relative contribution of mPGES-1 and 5-LOX to colon tumor developmen;t 3). Determine whether combinational targeting of mPGES-1/5-LOX with statin would improve the colon tumor inhibition efficacy and reduce cardiovascular side effects compared with celecoxib, and; 4). Determine the potential CV risk, if any, of long-term administration of CDPDPA compared with Celecoxib in LDLr-/-ApoB100/100 mice. The completion of this project will significantly improve the safety and efficacy of this novel drug for the prevention and treatment of CRC.