Comprehensive Analysis of UGT1A Polymorphisms Predictive for Pharmacokinetics and Treatment Outcome in Patients With Non–Small-Cell Lung Cancer Treated With Irinotecan and Cisplatin

摘要: Purpose To determine whether uridine diphosphate-glucuronosyltransferase 1A1, UGT1A7, and UGT1A9 polymorphisms affect the pharmacokinetics (PK) of irinotecan treatment outcome Korean patients with advanced non–small-cell lung cancer (NSCLC). Methods Eighty-one NSCLC were treated (80 mg/m 2 )o n day 1a nd 8 cisplatin (60 ) on 1 intravenously each 3-week cycle. Genomic DNA was extracted from peripheral blood genotyped using direct sequencing. We analyzed association UGT1A genotypes PK clinical outcomes. All statistical tests two-sided. Results In genotype-PK analysis, UGT1A1*6/*6 (n 6), UGT1A7*3/*3 UGT1A9118(dT)9/9 11) associated significantly lower area under time-concentration curve (AUC) SN-38G to SN-38 (AUCSN-38G/AUCSN-38) ratio (P .002, P .009, .001, respectively). linkage disequilibrium UGT1A7 variants highly linked UGT1A1*6 (D 0.85, r 0.63) UGT1A9*22 0.95, 0.88), which substantiated in haplotype analysis. Patients had tumor response higher incidence severe neutropenia. UGT1A9-118(dT)9/9 also showed a trend for high diarrhea, but not response. survival shorter progression-free .001) overall .017). Conclusion These findings suggest that may be important glucuronidation associate irinotecan-related toxicity. Specifically, might useful predicting irinotecan-based chemotherapy.