@article {Innocenti596, author = {Federico Innocenti and Lalitha Iyer and Mark J. Ratain}, title = {Pharmacogenetics of Anticancer Agents: Lessons from Amonafide and Irinotecan}, volume = {29}, number = {4}, pages = {596--600}, year = {2001}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Amonafide and irinotecan are anticancer drugs representative of the clinical relevance of N-acetyltransferase (NAT) and uridine diphosphate glucuronosyltransferase (UGT) polymorphisms in cancer chemotherapy, respectively. Amonafide, a substrate for the polymorphic NAT2, has an active metabolite, N-acetyl-amonafide. Using caffeine as a probe, slow and rapid acetylators of amonafide were identified. Fast acetylators experienced greater myelosuppression than did slow acetylators, and a reduced dose of amonafide for fast acetylators has been recommended. A pharmacodynamic model based on acetylator phenotype, pretreatment white blood cell count, and gender has been proposed for dose individualization. The strategy adopted for amonafide is a model for future investigations in pharmacogenetics, although amonafide is no longer 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 Crigler-Najjar and Gilbert{\textquoteright}s syndromes characterized by unconjugated hyperbilirubinemia. Gilbert{\textquoteright}s syndrome often remains undiagnosed and occurs in up to 19\% of individuals. Gilbert{\textquoteright}s syndrome is due to a homozygous TA insertion 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 obtained from individuals carrying the (TA)7 allele. A phenotyping procedure for UGT1A1 has not been identified and genotyping of theUGT1A1 promoter in patients receiving irinotecan may identify patients at increased risk of toxicity. A clinical trial at the University of Chicago is ongoing to demonstrate the predictive significance of UGT1A1 genotyping for irinotecan pharmacodynamics. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/29/4/596}, eprint = {https://dmd.aspetjournals.org/content/29/4/596.full.pdf}, journal = {Drug Metabolism and Disposition} }