Clinical pharmacogenetics of irinotecan (CPT-11)

Abstract

Irinotecan (CPT-11) is now widely used, especially for colorectal and lung cancers, whereas the drug causes severe adverse drug reactions (ADR), such as leukopenia/neutropenia or diarrhea. Irinotecan undergoes drug metabolism to form an active SN-38, which is further converted to its beta-glucuronide by UDP-glucuronosyltransferase (UGT) 1A1. A variant in the promoter of UGT1A1 gene, UGT1A1*28 allele, has been extensively studied, and pharmacogenetic relationships between the variant and ADR to irinotecan have been reported. A case-control study of Japanese cancer patients demonstrated that the patients having UGT1A1*28 were at significantly increased risk of severe ADR to irinotecan. To date, genetic variations of the UGT1A1 gene is the most important hereditary factor to predict severe ADR to irinotecan. The UGT1A1*28 is the only one variant that has multiple lines of clinical evidence in multiple races, whereas genetic variations of other UGT isoforms, drug-metabolizing enzymes and drug transporters need more confirmations of its clinical significance in multiple patient groups. At present, irinotecan chemotherapy based on a patient's UGT1A1 genetic status is scientifically reasonable.