Development of Novel Drugs to Alleviate CPT-11 Toxicity

描述（由申请人提供）：（伊立替康）是一种广泛使用的化学治疗前药，由于其强烈的剂量限制性副作用腹泻，其临床效用受到限制。几种方法都未能充分降低这种毒性。CPT-11诱导的腹泻的药理学表明，存在于肠腔内的微生物β-葡萄糖醛酸酶从无活性SN-38-葡萄糖醛酸酯原位产生活性代谢产物SN- 38。我们最近阐明了E.杆菌 β-葡萄糖醛酸酶，并发现了几种高效的抑制剂有效的活细菌菌株。随后在小鼠中的研究表明，一种这样的抑制剂Inh 1保护小鼠免受CPT-11诱导的毒性（Wallace等人，Science 2010，in press）.该提议的中心假设是，CPT-11的抗肿瘤活性可以使用新型胃肠道（GI）细菌靶向先导化合物来改善。这一假设是基于降低GI毒性将导致 给予递增剂量的CPT-11，从而改善暴露和抗肿瘤活性。这一发现的长期目标是了解微生物β-葡萄糖醛酸苷酶在异生物质和内生代谢、毒性和致癌作用中的作用。该提案的目的是完成有前途的先导化合物Inh 1的基本临床前体内药理学和疗效研究，因为它与CPT-11有关（目标2和3）。此外，其他新型细菌β-葡萄糖醛酸酶抑制剂将在体外、细胞和小鼠研究中进行检查和表征（目的1）。用于完成这些目标的方法包括了解Inh 1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。将使用小鼠中的新型异种移植人结肠肿瘤来确定Inh 1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的β-葡萄糖醛酸酶抑制剂将在体外和体内进行评价。新的化合物合成可能是必要的，以优化交付，同时保持效力。这些目的和目标与NCI的使命一致，NCI专注于改善癌症治疗的机械方法。我们的目标是通过减轻其剂量限制性副作用来提高CPT-11的功效。

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 ß-glucuronidase residing within the gut lumen. We recently elucidated the crystal structure of E. coli ß-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 ß-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 ß-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 ß-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.