Role of UGT1A16, UGT1A128 and ABCG2 c.421C>A polymorphisms in irinotecan‐induced neutropenia in Asian cancer patients

• Published in: Cancer science Vol. 98; no. 9; pp. 1461 - 1467
• Main Authors: Jada, Srinivasa Rao, Lim, Robert, Wong, Chiung Ing, Shu, Xiaochen, Lee, Soo Chin, Zhou, Qingyu, Goh, Boon Cher, Chowbay, Balram
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01-09-2007; Blackwell
• Subjects: Adult; Aged; Alleles; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - physiology; Biological and medical sciences; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Female; Genetic Predisposition to Disease; Glucuronosyltransferase - genetics; Glucuronosyltransferase - physiology; Hematologic and hematopoietic diseases; Humans; India - epidemiology; Irinotecan; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Malaysia - epidemiology; Male; Medical sciences; Middle Aged; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neutropenia - chemically induced; Neutropenia - epidemiology; Neutropenia - genetics; Original; Other diseases. Hematologic involvement in other diseases; Polymorphism, Genetic; Singapore - epidemiology; Tumors; Urogenital Neoplasms - drug therapy; Urogenital Neoplasms - genetics; Antineoplastic agent; Human; Treatment resistance; Asiatic; Genetic variability; Leukopenia; Enzyme; DNA topoisomerase; Enzyme inhibitor; Genotype; Hemopathy; Malignant tumor; Irinotecan; ABCG2 gene; Isomerases; Cancerology; ABC transporter; Neutropenia; Polymorphism; Cancer
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2007.00541.x

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/m2 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/µL) 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. (Cancer Sci 2007; 98: 1461–1467)