Safer Approaches to CRC Chemoprevention

项目摘要 这项研究的主要目的是开发基于机制的，有效的， 结直肠癌（CRC）化学预防的更安全的药物。 每年约有15万美国人被诊断出患有结直肠癌（CRC），这是美国结直肠癌患者中的第二大癌症。 美国癌症相关死亡的原因。全世界约有135万新的CRC病例被诊断出来， 强调儿童权利委员会是一个重大的健康问题。我们小组和其他人的证据表明， 并且选择的考克斯-2抑制剂在临床前模型和CRC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）风险相关。 这些风险的原因包括5-LOX代谢物增加和PGI 2合成减少。因此，在本发明中， 选择性靶向微粒体PG合成酶-1（mPGES-1）和5-LOX将阻断促肿瘤发生。 PGE 2/血栓前LT，但保留PGI 2。这种方法是开发高效和更安全的CRC的理想方法 化学预防剂为此，通过高通量和酶动力学测定和短- 在体内有效性研究方面，我们发现了一种新的双重mPGES-1 /5-LOX抑制剂，CDPDPA。在这 根据建议，我们寻求进一步开发CDPDPA用于CRC化学预防。我们设计了一项研究， 评估药效学剂量反应疗效的策略，了解mPGES-1/5的作用， LOX，通过组合方法提高疗效和安全性，并评估CV风险（如有）， CDPDPA与考克斯-2抑制剂比较。我们组建了一个具有CRC专业知识的团队 化学预防和心血管研究进行以下目标。1）。确定目标是否 mPGES-1和5-LOX与CDPDPA在AOM诱导的大鼠结肠腺癌中均有效 2）确定mPGES-1和5-LOX对结肠肿瘤的来源和相对贡献 developmen;t 3）.确定mPGES-1/5-LOX与他汀类药物的联合靶向是否会改善 与塞来昔布相比，结肠肿瘤抑制功效和降低心血管副作用; 4）。确定CDPDPA长期给药与塞来昔布相比的潜在CV风险（如有） 在LDLr-/-ApoB 100/100小鼠中。该项目的完成将显著提高 这种用于预防和治疗CRC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.