Document Detail


Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients.
MedLine Citation:
PMID:  17627617     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 < or = 500/microL) 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.
Authors:
Srinivasa Rao Jada; Robert Lim; Chiung Ing Wong; Xiaochen Shu; Soo Chin Lee; Qingyu Zhou; Boon Cher Goh; Balram Chowbay
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-07-11
Journal Detail:
Title:  Cancer science     Volume:  98     ISSN:  1347-9032     ISO Abbreviation:  Cancer Sci.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-13     Completed Date:  2007-10-17     Revised Date:  2014-03-28    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  1461-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics*,  physiology
Adult
Aged
Alleles*
Camptothecin / adverse effects,  analogs & derivatives*,  therapeutic use
Carcinoma, Non-Small-Cell Lung / drug therapy,  genetics
Colorectal Neoplasms / drug therapy,  genetics
Female
Genetic Predisposition to Disease
Glucuronosyltransferase / genetics*,  physiology
Humans
India / epidemiology
Lung Neoplasms / drug therapy,  genetics
Malaysia / epidemiology
Male
Middle Aged
Neoplasm Proteins / genetics*,  physiology
Neutropenia / chemically induced*,  epidemiology,  genetics*
Polymorphism, Genetic*
Singapore / epidemiology
Urogenital Neoplasms / drug therapy,  genetics
Chemical
Reg. No./Substance:
0/ABCG2 protein, human; 0/Neoplasm Proteins; 7673326042/irinotecan; EC 2.4.1.-/UGT1A1 enzyme; EC 2.4.1.17/Glucuronosyltransferase; XT3Z54Z28A/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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