Xu Shengkun, Lan Huiyin, Huang Chengyi, Ge Xingnan, Zhu Ji
Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China.
Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China.
Eur J Pharmacol. 2024 Jul 5;974:176614. doi: 10.1016/j.ejphar.2024.176614. Epub 2024 Apr 25.
Irinotecan (also known as CPT-11) is a topoisomerase I inhibitor first approved for clinical use as an anticancer agent in 1996. Over the past more than two decades, it has been widely used for combination regimens to treat various malignancies, especially in gastrointestinal and lung cancers. However, severe dose-limiting toxicities, especially gastrointestinal toxicity such as late-onset diarrhea, were frequently observed in irinotecan-based therapy, thus largely limiting the clinical application of this agent. Current knowledge regarding the pathogenesis of irinotecan-induced diarrhea is characterized by the complicated metabolism of irinotecan to its active metabolite SN-38 and inactive metabolite SN-38G. A series of enzymes and transporters were involved in these metabolic processes, including UGT1A1 and CYP3A4. Genetic polymorphisms of these metabolizing enzymes were significantly associated with the occurrence of irinotecan-induced diarrhea. Recent discoveries and progress made on the detailed mechanisms enable the identification of potential biomarkers for predicting diarrhea and as such guiding the proper patient selection with a better range of tolerant dosages. In this review, we introduce the metabolic process of irinotecan and describe the pathogenic mechanisms underlying irinotecan-induced diarrhea. Based on the mechanisms, we further outline the potential biomarkers for predicting the severity of diarrhea. Finally, based on the current experimental evidence in preclinical and clinical studies, we discuss and prospect the current and emerging strategies for the prevention of irinotecan-induced diarrhea.
伊立替康（也称为CPT-11）是一种拓扑异构酶I抑制剂，于1996年首次被批准作为抗癌药物用于临床。在过去的二十多年里，它被广泛用于联合治疗方案，以治疗各种恶性肿瘤，尤其是胃肠道癌和肺癌。然而，在基于伊立替康的治疗中，经常观察到严重的剂量限制性毒性，尤其是胃肠道毒性，如迟发性腹泻，这在很大程度上限制了该药物的临床应用。目前关于伊立替康诱导腹泻发病机制的认识特点是伊立替康复杂的代谢过程，即其代谢为活性代谢物SN-38和非活性代谢物SN-38G。一系列酶和转运体参与了这些代谢过程，包括UGT1A1和CYP3A4。这些代谢酶的基因多态性与伊立替康诱导腹泻的发生显著相关。最近在详细机制方面的发现和进展使得能够识别预测腹泻的潜在生物标志物，从而指导正确的患者选择，并确定更好的耐受剂量范围。在这篇综述中，我们介绍了伊立替康的代谢过程，并描述了伊立替康诱导腹泻的致病机制。基于这些机制，我们进一步概述了预测腹泻严重程度的潜在生物标志物。最后，基于目前临床前和临床研究的实验证据，我们讨论并展望了预防伊立替康诱导腹泻的现有和新兴策略。
