Role ofUGT1A1*6,UGT1A1*28andABCG2c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients
| Autor: | Chiung Ing Wong, Soo Chin Lee, Balram Chowbay, Boon Cher Goh, Qingyu Zhou, Robert Lim, Srinivasa Rao Jada, Xiaochen Shu |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Lung Neoplasms Neutropenia India Biology Irinotecan Gastroenterology Carcinoma Non-Small-Cell Lung Internal medicine Genotype medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Genetic Predisposition to Disease Glucuronosyltransferase Allele Alleles Aged Singapore Polymorphism Genetic Leukopenia Malaysia Cancer General Medicine Middle Aged medicine.disease Neoplasm Proteins Oncology Immunology Absolute neutrophil count ATP-Binding Cassette Transporters Camptothecin Female medicine.symptom Colorectal Neoplasms Urogenital Neoplasms Pharmacogenetics medicine.drug |
| Zdroj: | Cancer Science. 98:1461-1467 |
| ISSN: | 1349-7006 1347-9032 |
| DOI: | 10.1111/j.1349-7006.2007.00541.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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