Selective inhibitors to improve CPT-11 therapy

选择性抑制剂改善 CPT-11 治疗

基本信息

批准号：
7992106
负责人：
PHILIP M POTTER
金额：
$ 32.4万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992106
关键词：
Acetylcholinesterase Adult Adverse drug effect Affinity Animal Model Animals Antineoplastic Agents Bile fluid Biochemical Biochemistry Biological Butyrylcholinesterase Camptothecin Carboxylic Ester Hydrolases Cell Culture Techniques Child Childhood Cholesterol Esters Cocaine Colon Carcinoma Complex Mixtures Crystallography Development Diarrhea Dose Dose-Limiting Engineering Enzyme Inhibition Enzymes Evaluation Goals Half-Life Heroin Hour Human Hydrolysis In Vitro Incidence Intestines Knock-in Mouse Lipids Liver Malignant Neoplasms Meperidine Metabolism Methods Modeling Mus Pediatric Neoplasm Pharmaceutical Chemistry Pharmaceutical Preparations Plant Resins Plasma Poison Procaine Prodrugs Property Proteins Quantitative Structure-Activity Relationship Reagent Resistance Ritalin SN-38 Severities Small Intestines Street Drugs Testing Therapeutic Toxic effect Type I DNA Topoisomerases Water Xenograft procedure analog antitumor agent base benzil cancer therapy carboxylesterase chemotherapeutic agent design esterase improved in vivo inhibitor/antagonist mouse model novel public health relevance research study response small molecule tumor

项目摘要

DESCRIPTION (provided by applicant): CPT-11 is a highly effective, camptothecin-based anticancer agent that is currently approved for the treatment of colon cancer. This compound is a prodrug and is activated by carboxylesterases to yield SN-38, a potent topoisomerase I poison. The dose limiting toxicity for CPT-11 is delayed diarrhea that occurs 48-96 hours following administration. This is thought to arise, in part, from direct activation of CPT-11, that is secreted in the bile, by a human intestinal carboxylesterase (CE) that is highly expressed in the small intestine. We hypothesize that by inhibiting this enzyme, reduced SN-38 will be produced from drug hydrolysis in the gut, thereby reducing the toxicity associated with CPT-11 treatment. The goals of this application are therefore to develop selective CE inhibitors that can be used to ameliorate the toxicity associated with CPT-11 administration. Highly potent, non-toxic small molecule inhibitors based upon the prototypical compound benzil have been identified, and we propose to develop these agents for use in inhibition of the human intestinal CE (hiCE). NMR, x-ray crystallography, medicinal chemistry, QSAR, biochemical and in vivo approaches will all be employed to validate the efficacy of suitable compounds The specific aims of this application are: 1) to determine the mechanism of CE inhibition by benzil; 2) to develop water-soluble analogues of benzil; 3) to assess the biochemical and biological properties of these compounds; and 4) assess their efficacy at modulating CPT-11-induced toxicity in a plasma esterase-deficient mouse model where hiCE is expressed in the mouse intestine. We believe that, if successful, these studies will provide reagents that can ameliorate the delayed diarrhea associated with CPT-11 administration, and potentially allow dose intensification of the drug. This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent. PUBLIC HEALTH RELEVANCE: These studies will identify and characterize novel drugs that can reduce the toxicity associated with CPT-11 treatment. Since this chemotherapeutic agent is widely used for cancer therapy, any approaches that reduce the side-effects of this drug will be highly desirable. We propose to develop such compounds that should have applicability to a wide variety of malignancies.

描述（由申请人提供）：CPT-11是一种高效的基于camptothecin的抗癌药，目前已被批准用于治疗结肠癌。该化合物是一种前药，被羧酸酯酶激活以产生SN-38，这是一种有效的拓扑异构酶I毒药。 CPT-11的剂量限制毒性是延迟的腹泻，在给药后48-96小时发生。人们认为这部分是由于人类肠道羧酸酯酶（CE）在胆汁中分泌的CPT-11的直接激活，该激活在小肠中高度表达。我们假设，通过抑制这种酶，将通过肠道中的药物水解产生降低的SN-38，从而降低与CPT-11治疗相关的毒性。因此，本应用的目标是开发可用于改善与CPT-11给药相关的毒性的选择性CE抑制剂。已经确定了基于原型化合物奔驰的高效，无毒的小分子抑制剂，我们建议开发这些药物以抑制人类肠道CE（HICE）。 NMR，X射线晶体学，药物化学，QSAR，生化和体内方法都将用于验证合适化合物的疗效。该应用的具体目的是：1）确定Benzil CE抑制的机理； 2）开发苯兹尔的水溶性类似物； 3）评估这些化合物的生化和生物学特性； 4）评估它们在调节CPT-11诱导的毒性中的疗效，在小鼠肠中表达hICE的血浆酯酶缺陷小鼠模型。我们认为，如果成功的话，这些研究将提供可以改善与CPT-11给药相关的延迟腹泻的试剂，并有可能允许该药物加强剂量。这可能会提高抗肿瘤疗效，此外，也可能允许使用该CPT-11来抵抗更具抵抗力的恶性肿瘤，以证明对该药物的边际反应。公共卫生相关性：这些研究将确定并表征可以减少与CPT-11治疗相关的毒性的新型药物。由于这种化学治疗剂被广泛用于癌症治疗，因此，任何降低该药物副作用的方法都是非常可取的。我们建议开发这种化合物，这些化合物应该适用于各种恶性肿瘤。