UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity
UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity
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DOI：
10.1038/sj.tpj.6500072
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发表时间：
2002-01-01
影响因子：
2.8
通讯作者：
Ratain, M. J.
中科院分区：
文献类型：
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作者：
Iyer, L.;Das, S.;Ratain, M. J.
伊立替康(CPT-11)的代谢包括对SN-38的顺序激活和对药理上无效的SN-38葡萄糖醛酸苷(SN-38G)的解毒。我们以前已经证明了UGT1A1酶在SN-38的葡萄糖醛酸化中的作用，以及SN-38的体外葡萄糖醛酸化与UGT1A1基因启动子的多态性之间存在显著的相关性。这种多态(UGT1A1*28)的特征是在UGT1A1启动子的TATA序列中存在额外的TA重复序列，((TA)7TAA，而不是(TA)6TAA)。在这里，我们报告了一项前瞻性临床药物遗传学研究的结果，以确定UGT1A1*28基因多态性对癌症患者伊立替康处置和毒性的意义。对20例实体瘤患者进行了90min静注治疗。伊立替康300 mg·m~(-2)静脉滴注，每3周1次。(TA)7TAA和(TA)6TAA的等位基因频率分别为0.375和0.625。携带(TA)7TAA多态的患者SN-38葡萄糖醛酸化频率显著低于正常等位基因(6/6>；6/7>；7/7，P=0.001)。仅在(TA)7TAA序列的杂合子(4级腹泻，n=1)或纯合子(3级腹泻/4级中性粒细胞减少症，n=1和3级中性粒细胞减少症，n=1)患者中观察到更严重的腹泻和中性粒细胞减少症。结果提示，筛查UGT1A1*28基因多态性可发现SN-38葡萄糖醛酸化频率较低、对伊立替康引起的胃肠道和骨髓毒性易感性较高的患者。
The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m-2) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6-45%, 6/7-35% and 7/7-20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P=0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n=1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n=1 and grade 3 neutropenia, n=1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.