Pharmacogenetics of anticancer agents: Lessons from amonafide and irinotecan

Amonafide and irinotecan are anticancer drugs representative of the clinica l relevance of N-acetyltransferase (NAT) and uridine diphosphate glucuronos yltransferase (UGT) polymorphisms in cancer chemotherapy, respectively. Amo nafide, a substrate for the polymorphic NAT2, has an active metabolite, N-a cetyl-amonafide. Using caffeine as a probe, slow and rapid acetylators of a monafide were identified. Fast acetylators experienced greater myelosuppres sion than did slow acetylators, and a reduced dose of amonafide for fast ac etylators has been recommended. A pharmacodynamic model based on acetylator phenotype, pretreatment white blood cell count, and gender has been propos ed for dose individualization. The strategy adopted for amonafide is a mode l for future investigations in pharmacogenetics, although amonafide is no l onger in clinical development. SN-38, the active metabolite of irinotecan, is glucuronidated to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Genetic defects in UGT1A1 determine C rigler-Najjar and Gilbert's syndromes characterized by unconjugated hyperbi lirubinemia. Gilbert's syndrome often remains undiagnosed and occurs in up to 19% of individuals. Gilbert's syndrome is due to a homozygous TA inserti on in the TATAA promoter of UGT1A1, leading to the mutated (TA)(7) allele. Irinotecan toxicity depends on the individual glucuronidation rate of SN-38 . Decreased SN-38 glucuronidating activity has been found in livers obtaine d from individuals carrying the (TA)(7) allele. A phenotyping procedure for UGT1A1 has not been identified and genotyping of the UGT1A1 promoter in pa tients receiving irinotecan may identify patients at increased risk of toxi city. A clinical trial at the University of Chicago is ongoing to demonstra te the predictive significance of UGT1A1 genotyping for irinotecan pharmaco dynamics.