Development of Novel Drugs to Alleviate CPT-11 Toxicity

开发减轻CPT-11毒性的新药

基本信息

批准号：
8634061
负责人：
Sridhar Mani
金额：
$ 31.8万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634061
关键词：
Acute Address Adverse effects Antineoplastic Agents Bacteria Beta-glucuronidase Biliary Cells Chemicals Clinical Colon Carcinoma Colonic Neoplasms Complex Data Development Diarrhea Dose Dose-Limiting Drug Kinetics Duct (organ) structure Ensure Enzymes Epithelial Cells Escherichia coli Evaluation Exhibits Gastrointestinal tract structure Glucuronidase Inhibitor Glucuronides Glucuronosyltransferase Goals Health Human In Situ In Vitro Intestines Lead Life Liver Malignant Neoplasms Metabolism Methodology Mission Molecular Biology Morphine Mus Oral Oral Administration Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Play Principal Investigator Prodrugs Production Publishing Rodent Role SN-38 SN-38G Science Solid Structure Therapeutic Time Toxic effect Vorinostat Work Xenobiotics base cancer therapy carcinogenesis chemotherapeutic agent commensal microbes enzyme activity esterase gastrointestinal gastrointestinal bacteria high throughput screening improved in vivo inhibitor/antagonist irinotecan killings microbial microbial host novel novel therapeutics pre-clinical preclinical study programs response stem tumor

项目摘要

DESCRIPTION (provided by applicant): (Irinotecan) is a widely used chemotherapeutic prodrug that exhibits curtailed clinical utility due to its intense dose-limiting side-effect, diarhea. Several approaches have failed to adequately reduce this toxicity. The pharmacology of CPT-11-induced diarrhea implicates the in situ production of the active metabolite, SN- 38, from inactive SN-38-glucuronde by microbial ?-glucuronidase residing within the gut lumen. We recently elucidated the crystal structure of E. coli ?-glucuronidase and discovered several high potency inhibitors effective in living bacterial strains. Subsequent studies in mice showed that one such inhibitor, Inh1, protected mice from CPT-11 induced toxicity (Wallace et al., Science 2010, in press). The central hypothesis for this proposal is that CPT-11 anti-tumor activity can be improved using novel gastrointestinal (GI) bacteria-targeted lead compounds. This hypothesis has been formulated on the rationale that reduced GI toxicity will result in the ability to administer escalated doses of CPT-11, thereby improving exposure and anti-tumor activity. The long- term objectives stemming from this discovery are to understand the roles microbial ?-glucuronidases play in xenobiotic and endobiotic metabolism, toxicity and carcinogenesis. The aims of this proposal are to complete the essential preclinical in vivo pharmacology and efficacy studies of the promising lead compound, Inh1, as it relates to CPT-11 (Aims 2 & 3). In addition, other novel bacterial ?-glucuronidase inhibitors will be examined and characterized in in vitro, cell- and mouse-based studies (Aim 1). The methodologies used to complete these aims include an understanding of the pharmacokinetics and pharmacodynamics of Inh1 as its relates to CPT-11 metabolism in rodents. Novel heterotransplanted human colon tumors in mice will be used to determine the effect of Inh1 on CPT-11 dose-intensification and anti-tumor activity. Finally, novel uncharacterized ?-glucuronidase inhibitors we have already discovered will be evaluated in vitro and in vivo. New compound synthesis may be necessary to optimize delivery while preserving potency. These aims and goals are in keeping with the mission of NCI, which is focused on mechanistic approaches towards improving cancer therapies. Our objective is to improve CPT-11 efficacy by alleviating its dose-limiting side effect.

描述（由申请人提供）：（ Irinotecan）是一种广泛使用的化学治疗前药，由于其强烈的剂量限制副作用，腹泻，表现出限制的临床实用性。几种方法无法充分降低这种毒性。 CPT-11诱导的腹泻的药理学暗示了活性代谢产物Sn-38的原位产生，从微生物中的无活性SN-38-葡萄糖葡萄糖酶？ - 葡萄糖醛酸酶驻留在肠道内。我们最近阐明了大肠杆菌？ - 葡萄糖醛酸酶的晶体结构，并发现了有效的几种高效力抑制剂，可有效。随后在小鼠中进行的研究表明，一种这样的抑制剂INH1保护小鼠免受CPT-11诱导毒性的影响（Wallace等，Science，2010年，印刷中）。该提议的中心假设是CPT-11抗肿瘤活性可以使用新型的胃肠道（GI）细菌的铅化合物来改善。该假设是基于理由，即gi毒性降低将导致能力为了施用升级的CPT-11剂量，从而改善了暴露和抗肿瘤活性。这一发现所产生的长期目标是了解微生物的作用？ - 葡萄糖醛酸苷酶在异种生物和内生物代谢，毒性和致癌作用中发挥作用。该提案的目的是完成与CPT-11相关的有前途的铅化合物INH1的体内药理学和疗效研究（AIMS 2和3）。此外，将在体外，基于细胞和小鼠的研究中检查和表征其他新型细菌？ - 葡萄糖醛酸酶抑制剂（AIM 1）。用于完成这些目标的方法包括了解INH1的药代动力学和药效学，因为它与啮齿动物中的CPT-11代谢有关。小鼠中新型的异质移植的人类结肠肿瘤将用于确定INH1对CPT-11剂量强化和抗肿瘤活性的影响。最后，我们已经发现的新型未表征？ - 葡萄糖醛酸苷酶抑制剂将在体外和体内进行评估。在保留效力的同时，可能需要新的化合物合成。这些目标和目标与NCI的使命保持一致，NCI的任务侧重于改善癌症疗法的机械方法。我们的目标是通过减轻限制剂量的副作用来提高CPT-11的功效。