Clinical pharmacogenetics of irinotecan (CPT-11)
Clinical pharmacogenetics of irinotecan (CPT-11)
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DOI：
10.1080/03602530500316254
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发表时间：
2005-01-01
影响因子：
5.9
通讯作者：
Hasegawa, Y
中科院分区：
文献类型：
--
作者：
Ando, Y;Hasegawa, Y
伊立替康(CPT-11)现在被广泛使用，特别是用于结直肠癌和肺癌，但该药物会导致严重的药物不良反应(ADR)，如白细胞减少/神经减少或腹泻。伊立替康通过药物代谢形成具有活性的SN-38，在UDP-葡萄糖醛酸基转移酶(UGT)1A1作用下进一步转化为β-葡萄糖醛酸苷。UGT1A1基因启动子的一个变异UGT1A1*28等位基因已被广泛研究，并已报道该变异与伊立替康的不良反应之间的药物遗传学关系。一项对日本癌症患者的病例对照研究表明，携带UGT1A1*28基因的患者对伊立替康的严重不良反应风险显著增加。迄今为止，UGT1A1基因的遗传变异是预测伊立替康严重不良反应的最重要的遗传因素。UGT1A1*28是唯一一个在多个种族中具有多条临床证据的变异，而其他UGT亚型、药物代谢酶和药物转运蛋白的遗传变异需要在多个患者组中更多地证实其临床意义。目前，根据患者的UGT1A1基因状态进行伊立替康化疗是科学合理的。
Irinotecan (CPT-11) is now widely used, especially for colorectal and lung cancers, whereas the drug causes severe adverse drug reactions (ADR), such as leukopenia/ neuropenia or diarrhea. Irinotecan undergoes drug metabolism to form an active SN-38, which is further converted to its beta-glucuronide by UDP-glucuronosyltransferase (UGT) 1A1. A variant in the promoter of UGT1A1 gene, UGT1A1*28 allele, has been extensively studied, and pharmacogenetic relationships between the variant and ADR to irinotecan have been reported. A case-control study of Japanese cancer patients demonstrated that the patients having UGT1A1*28 were at significantly increased risk of severe ADR to irinotecan. To date, genetic variations of the UGT1A1 gene is the most important hereditary factor to predict severe ADR to irinotecan. The UGT1A1*28 is the only one variant that has multiple lines of clinical evidence in multiple races, whereas genetic variations of other UGT isoforms, drug-metabolizing enzymes and drug transporters need more confirmations of its clinical significance in multiple patient groups. At present, irinotecan chemotherapy based on a patient's UGT1A1 genetic status is scientifically reasonable.