Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients

被引:102
作者
Jada, Srinivasa Rao
Lim, Robert
Wong, Chiung Ing
Shu, Xiaochen
Lee, Soo Chin
Zhou, Qingyu
Goh, Boon Cher
Chowbay, Balram
机构
[1] Natl Canc Ctr, Humphrey Oei Inst Canc Res, Div Med Sci, LabClin Pharmacol, Singapore 169610, Singapore
[2] Natl Univ Singapore Hosp, Dept Haematol & Oncol, Singapore 119074, Singapore
来源
CANCER SCIENCE | 2007年 / 98卷 / 09期
关键词
PHASE-II TRIAL; UDP-GLUCURONOSYLTRANSFERASE; COLORECTAL-CANCER; PHARMACOKINETICS; SN-38; METABOLITE; GLUCURONIDATION; CISPLATIN; PATHWAY; CPT-11;
D O I
10.1111/j.1349-7006.2007.00541.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The objectives of the present study were (i) to study the pharmacogenetics of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C > A in three distinct healthy Asian populations (Chinese, Malays and Indians), and (ii) to investigate the polygenic influence of these polymorphic variants in irinotecan-induced neutropenia in Asian cancer patients. Pharmacokinetic and pharmacogenetic analyses were done after administration of irinotecan as a 90-min intravenous infusion of 375 mg/m(2) once every 3 weeks (n = 45). Genotypic-phenotypic correlates showed a non-significant influence of UGT1A1*28 and ABCG2 c.421C > A polymorphisms on the pharmacokinetics of SN-38 (P > 0.05), as well as severity of neutropenia (P > 0.05). Significantly higher exposure levels to SN-38 (P = 0.018), lower relative extent of glucuronidation (REG; P = 0.006) and higher biliary index (BI; P = 0.003) were found in cancer patients homozygous for the UGT1A1*6 allele compared with patients harboring the reference genotype. The mean absolute neutrophil count (ANC) was 85% lower and the prevalence of grade 4 neutropenia (ANC <= 500/mu L) was 27% in patients homozygous for UGT1A1*6 compared with the reference group. Furthermore, the presence of the UGT1A1*6 allele was associated with an approximately 3-fold increased risk of developing severe grade 4 neutropenia compared with patients harboring the reference genotype. These exploratory findings suggest that homozygosity for UGT1A1*6 allele may be associated with altered SN-38 disposition and may increase the risk of severe neutropenia in Asian cancer patients, particularly in the Chinese cancer patients who comprised 80% (n = 36) of the patient population in the present study.
引用
收藏
页码:1461 / 1467
页数:7
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