Alimonti Andrea, Gelibter Alain, Pavese Ida, Satta Francesco, Cognetti Francesco, Ferretti Gianluigi, Rasio Debora, Vecchione Aldo, Di Palma Mario
Division of Medical Oncology, San Pietro Hospital, FBF International, Rome, Italy.
Cancer Treat Rev. 2004 Oct;30(6):555-62. doi: 10.1016/j.ctrv.2004.05.002.
Irinotecan is a selective inhibitor of topoisomerase I, an enzyme part of the replication and transcription system of DNA. Irinotecan is employed, with different modalities, in the treatment of metastatic colorectal cancer, and recently it has been officially approved in association with fluorouracil (FU) and leucovorin (LV) as a first-line option in metastatic colorectal cancer.
One of the problems linked to the administration of this drug is the high intestinal toxicity, which constitutes its dose limiting toxicity (DLT). In routine practice, loperamide is employed as symptomatic drug for the treatment of CPT-11-induced diarrhoea, but is not completely adequate to control the problem. The role of the intestinal bacterial microflora in the pathogenesis of CPT-11-induced intestinal toxicity has been recently discovered. The active metabolite of CPT-11, SN38, is generated from CPT-11 by sieric carboxylesterase, and subsequently conjugated to SN38-G by hepatic UDP-glucuronyltransferase. SN38-G is the inactive metabolite of CPT-11 and is excreted into the small intestine, from which it is eliminated in the faeces. Some studies have shown the ability of intestinal bacterial beta-glucoronidases to transform SN38-G into SN38, causing direct damage to the intestinal mucosa. Thus, alternative strategies such as intestinal alkalinization and anti-cyclooxygenase 2 (COX-2) therapy have been explored.
In this review, we will illustrate the mechanisms which cause the CPT-11-induced diarrhoea and the potential measures available to prevent it.
伊立替康是拓扑异构酶I的选择性抑制剂，拓扑异构酶I是DNA复制和转录系统的一种酶。伊立替康以不同方式用于治疗转移性结直肠癌，最近它已被正式批准与氟尿嘧啶（FU）和亚叶酸（LV）联合作为转移性结直肠癌的一线治疗方案。
与该药物给药相关的问题之一是高肠道毒性，这构成了其剂量限制毒性（DLT）。在常规实践中，洛哌丁胺被用作治疗CPT-11诱导腹泻的对症药物，但并不完全足以控制该问题。肠道细菌微生物群在CPT-11诱导的肠道毒性发病机制中的作用最近已被发现。CPT-11的活性代谢产物SN38由CPT-11通过血清羧酸酯酶产生，随后通过肝脏UDP-葡萄糖醛酸转移酶与SN38-G结合。SN38-G是CPT-11的无活性代谢产物，排泄到小肠中，然后随粪便排出。一些研究表明肠道细菌β-葡萄糖醛酸酶能够将SN38-G转化为SN38，对肠黏膜造成直接损伤。因此，人们探索了诸如肠道碱化和抗环氧化酶2（COX-2）治疗等替代策略。
在本综述中，我们将阐述导致CPT-11诱导腹泻的机制以及可用于预防腹泻的潜在措施。
