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疗前药，由于其强烈的剂量限制副作用，腹泻，临床应用受到限制。有几种方法未能充分降低这种毒性。cpt -11诱导腹泻的药理学表明，肠道内的微生物ß-葡萄糖醛酸酶可从无活性的SN-38-葡糖苷酸就地产生活性代谢物SN-38。我们最近阐明了大肠杆菌的晶体结构

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.