Selective inhibitors to improve CPT-11 therapy

描述(申请人提供)：CPT-11是一种高效的、基于喜树碱的抗癌药物，目前被批准用于治疗结肠癌。该化合物是一种前体药物，被羧酸酯酶激活而产生SN-38，一种有效的拓扑异构酶I毒物。CPT-11的剂量限制毒性是迟发性腹泻，出现在给药后48-96小时。这在一定程度上被认为是由于胆汁中分泌的CPT-11被一种在小肠中高度表达的人类肠道羧酸酯酶(CE)直接激活。我们假设，通过抑制这种酶，减少的SN-38将产生肠道内的药物水解，从而减少与CPT-11治疗相关的毒性。因此，该应用的目标是开发选择性CE抑制剂，可用于改善与CPT-11给药相关的毒性。基于典型化合物BANIL的高效、无毒的小分子抑制剂已经被确定，我们建议开发这些药物用于抑制人类肠道CE(HICE)。本应用的具体目的是：1)确定BANIL抑制CE的机制；2)开发BANIL的水溶性类似物；3)评估这些化合物的生化和生物学特性；以及4)评估它们在调节CPT-11诱导的小鼠血浆酯酶缺乏模型中的毒性的有效性。我们相信，如果成功，这些研究将提供可以改善与CPT-11给药相关的延迟性腹泻的试剂，并有可能使药物的剂量增加。这可能会导致更好的抗肿瘤效果，此外，还可能使用这种CPT-11来治疗对这种药物表现出边际反应的更多耐药的恶性肿瘤。 公共卫生相关性：这些研究将确定和表征可以减少与CPT-11治疗相关的毒性的新药。由于这种化疗药物被广泛用于癌症治疗，任何减少这种药物副作用的方法都是非常可取的。我们建议开发这样的化合物，这些化合物应该适用于各种恶性肿瘤。

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.