de Jong Floris A, de Jonge Maja J A, Verweij Jaap, Mathijssen Ron H J
Department of Medical Oncology, Daniel den Hoed Cancer Center, Erasmus University Medical Center Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
Cancer Lett. 2006 Mar 8;234(1):90-106. doi: 10.1016/j.canlet.2005.04.040. Epub 2005 Dec 15.
In the treatment of advanced colorectal cancer, irinotecan has become one of the most important drugs, despite its sometimes unpredictable adverse effects. To understand why some patients experience severe adverse effects (diarrhea and neutropenia), while others do not, the metabolic pathways of this drug have to be unraveled in detail. Individual variation in expression of several phase I and phase II metabolizing enzymes and ABC-transporters involved in irinotecan metabolism and excretion, at least partly explains the observed pharmacokinetic interpatient variability. Although the difference in expression-level of these proteins to a certain amount is explained by physiologic and environmental factors, the presence of specific genetic determinants also does influence their expression and function. In this review, the role of genetic polymorphisms in the main enzyme-systems (carboxylesterase, cytochrome P450 3A, and uridine diphosphate-glucuronosyltransferase) and ABC-transporters (ABCB1, ABCC2, and ABCG2) involved in irinotecan metabolism, are discussed. Since at this moment the field of pharmacogenetics and pharmacogenomics is rapidly expanding and simultaneously more rapid and cost-effective screening methods are emerging, a wealth of future data is expected to enrich our knowledge of the genetic basis of irinotecan metabolism. Eventually, this may help to truly individualize the dosing of this (and other) anti-cancer agent(s), using a personal genetic profile of the most relevant enzymes for every patient.
在晚期结直肠癌的治疗中，伊立替康已成为最重要的药物之一，尽管其不良反应有时难以预测。为了理解为什么有些患者会出现严重不良反应（腹泻和中性粒细胞减少），而另一些患者则不会，必须详细阐明该药物的代谢途径。参与伊立替康代谢和排泄的几种I相和II相代谢酶及ABC转运蛋白表达的个体差异，至少部分解释了观察到的患者间药代动力学变异性。虽然这些蛋白质表达水平的差异在一定程度上可由生理和环境因素解释，但特定基因决定因素的存在也确实会影响它们的表达和功能。在这篇综述中，我们讨论了基因多态性在参与伊立替康代谢的主要酶系统（羧酸酯酶、细胞色素P450 3A和尿苷二磷酸葡萄糖醛酸转移酶）和ABC转运蛋白（ABCB1、ABCC2和ABCG2）中的作用。由于目前药物遗传学和药物基因组学领域正在迅速扩展，同时更快速且具成本效益的筛选方法不断涌现，预计未来会有大量数据丰富我们对伊立替康代谢遗传基础的认识。最终，这可能有助于根据每位患者最相关酶的个人基因概况，真正实现这种（及其他）抗癌药物给药的个体化。
