Irinotecan treatment in cancer patients with UGT1A1 polymorphisms

At the present time, pharmacogenetic investigation of irinotecan (CPT-11, Camptosar) therapy is mainly focused on the clinical relevance of genetic variation in the UDP-glucuronosyltransferase (UGT1A1) gene. The glucuronidation of the potent topoisomerase I inhibitor SN-38 is a major inactivation pathway of irinotecan metabolism. UGT1A1 genotypes associated with Gilbert's syndrome (a mild intermittent hyperbilirubinemia) are characterized by reduced glucuronidation of SN-38. Such UGT1A1 genetic variants have different distribution across individuals of different ethnicity. The (TA)n TAA polymorphism in the promoter is more frequent in Caucasians as compared to Asians, in whom missense polymorphisms in the exons are more common. Two recent pharmacogenetic trials (one performed in the United States and the other in Japan) investigated the clinical significance of UGT1A1 gene mutations for both the pharmacokinetics of irinotecan metabolites and the toxicity profile. The results of these association studies showed that preliminary genotyping of the (TA)n polymorphism might predict the occurrence of toxicity in genetically predisposed patients.