Development of Novel Drugs to Alleviate CPT-11 Toxicity

描述(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引起的腹泻的药理作用涉及肠道内的微生物通过非活性的SN-38-葡萄糖醛酸苷酶原位产生活性代谢物SN-38。我们最近阐明了大肠杆菌的晶体结构。 并发现了几种对活细菌菌株有效的高效抑制剂。随后在小鼠身上进行的研究表明，一种这样的抑制剂Inh1可以保护小鼠免受CPT-11诱导的毒性(Wallace等人，《科学》，2010年出版)。这一建议的中心假设是，CPT-11的抗肿瘤活性可以通过使用新的胃肠道(GI)细菌靶向先导化合物来改善。这一假设是建立在这样的理论基础上的：减少胃肠道毒性将导致 增加剂量的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和内生新陈代谢、毒性和致癌中所起的作用。这项提案的目的是完成与CPT-11相关的有前景的先导化合物Inh1的基本临床前体内药理和疗效研究(目标2和3)。此外，还将在体外、细胞和小鼠研究(目标1)中检验和表征其他新型细菌β-葡萄糖醛酸酶抑制剂。完成这些目标所使用的方法包括了解Inh1的药代动力学和药效学，因为它与CPT-11在啮齿动物体内的代谢有关。新型异种移植的小鼠人结肠肿瘤将被用来确定Inh1对CPT-11剂量增强和抗肿瘤活性的影响。最后，我们已经发现的新的未表征的β-葡萄糖醛酸酶抑制剂将在体外和体内进行评估。为了在保持效力的同时优化给药，新的化合物合成可能是必要的。这些目的和目标与NCI的使命是一致的，NCI专注于改善癌症治疗的机械性方法。我们的目标是通过减轻CPT-11的剂量限制性副作用来提高其疗效。

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.