Safer Approaches to CRC Chemoprevention

项目摘要 这项拟议的研究的主要目的是开发基于机械的、有效的和 更安全的结直肠癌(CRC)化学预防药物。 每年约有15万美国人被诊断出患有结直肠癌(CRC)，这是第二大癌症 美国癌症相关死亡的原因。全球约有135万新确诊的结直肠癌病例， 强调儿童权利公约是一个主要的健康问题。来自我们小组和其他人的证据表明，非甾体抗炎药 选择的COX-2抑制剂在临床前模型和结直肠癌患者中显示出显著的抑制作用， 但这些抑制剂也与胃肠道(GI)毒性和心血管(CV)风险有关。 这些风险的原因包括5-LOX代谢物增加和PGI2合成减少。因此， 选择性靶向微粒体PG合成酶-1(mPGES-1)和5-LOX可阻断肿瘤的发生 前列腺素E_2/血栓前状态，但不使用前列环素。这种方法非常适合开发高效且更安全的CRC 化学防护剂。为此，通过高通量和酶动力学分析和短期- 在体内疗效研究方面，我们发现了一种新型的双重mPGES-1/5-LOX抑制剂CDPDPA。在这 建议，我们寻求进一步开发用于结直肠癌化学预防的CDPDPA。我们设计了这项研究 评估药物动力学剂量反应效应的策略，了解mPGES-1/5- LOX，通过组合方法提高有效性和安全性，并评估心血管风险，如果有的话 CDPDPA与COX-2抑制剂的比较。我们已经组建了一支在CRC方面具有专业知识的团队 化学预防和心血管研究以实现以下目标。1)。确定目标是否为 MPGES-1和5-LOX联合CDPDPA对AOM诱导的大鼠结肠腺癌的治疗作用 治疗；2)确定mPGES-1和5-LOX在结肠癌中的来源和相对贡献 发展；t3)。确定mPGES-1/5-LOX与他汀类药物联合靶向是否会改善 与塞来昔布相比，在抑制结肠癌的疗效和减少心血管副作用方面，以及； 4)。与塞来昔布比较，确定长期服用CDPDPA的潜在心血管风险(如果有) 在LDLR-/-ApoB100/100小鼠中。该项目的建成将显著提高药物治疗的安全性和有效性。 这种预防和治疗结直肠癌的新药。

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.