Selective Inhibitors to Improve CPT-11 Therapy

选择性抑制剂改善 CPT-11 治疗

• 批准号: 6914121
• 负责人: PHILIP M POTTER
• 金额: $ 26.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914121
• 关键词: SCID mouse; camptothecin; carboxylic ester hydrolases; complementary DNA; diarrhea; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; gene expression; genetic models; genetic promoter element; genetically modified animals; model design /development; neoplasm /cancer chemotherapy; pharmacokinetics; prodrugs; tissue /cell culture

DESCRIPTION (provided by applicant): CPT-11 is a camptothecin derived prodrug that is activated by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I inhibitor. CPT-11 has demonstrated remarkable antitumor activity in animal models and is currently being used in clinical trials for a variety of human malignancies. The drug is activated in the liver and primarily excreted by deposition in the bile. However, the dose limiting toxicity for this drug is delayed diarrhea that occurs 24-96 hours following administration. Since the bile duct opens into the gut in the duodenum, the region of the intestine that demonstrates the highest levels of CE and CPT-11 converting activity, we propose that the diarrhea occurs via drug activation from the human intestinal CE (hiCE) present in the gut. In an attempt to ameliorate this toxicity, we have developed selective hiCE inhibitors. In this application, we will use a variety of molecular modeling and QSAR techniques to improve the potency of these compounds and determine the mechanism of enzyme inhibition by these novel chemicals. Finally, we will assess the efficacy of these agents towards reducing CPT-11-induced diarrhea in an animal model. The Specific Aims of this application are therefore to: 1) design and synthesize selective inhibitors based upon SAR analysis; 2) determine the mechanism of inhibition; 3) assess the ability of the novel inhibitors to selectively inhibit hiCE both in vitro and in cell culture systems; 4) generate a mouse model that results in expression of the hiCE cDNA under control of the mouse intestinal CE promoter; and 5) determine whether the novel inhibitors ameliorate CPT-11-induced diarrhea in this mouse model. Overall, these studies should allow development of selective inhibitors for use in combination with CPT-11 to reduce the toxicity of the drug. Additionally, such compounds may allow dose intensification of CPT-11 for improved cancer therapy.

描述（由申请人提供）：CPT-11是喜树碱衍生的前药，由羧酸酯酶（CE）激活产生SN-38，一种有效的拓扑异构酶I抑制剂。CPT-11在动物模型中显示出显著的抗肿瘤活性，目前正用于多种人类恶性肿瘤的临床试验。该药物在肝脏中被激活，主要通过在胆汁中的沉积排出。然而，该药物的剂量限制性毒性是在给药后24-96小时发生的迟发性腹泻。由于胆管通过十二指肠进入肠道，而十二指肠是肠道中CE和CPT-11转化活性最高的区域，因此我们认为腹泻是通过肠道中存在的人类肠道CE （hiCE）的药物激活发生的。为了改善这种毒性，我们开发了选择性hiCE抑制剂。在本应用中，我们将使用各种分子建模和QSAR技术来提高这些化合物的效力，并确定这些新化学物质对酶的抑制机制。最后，我们将在动物模型中评估这些药物对减少cpt -11诱导的腹泻的功效。