Pharmacogenetics - A tool for individualising antineoplastic therapy

This article reviews the clinical relevance of pharmacogenetics in cancer c hemotherapy, with emphasis on drugs for which genetic differences in enzyme metabolism have been demonstrated to affect patient outcome. About 10% of children with leukaemia are intolerant to mercaptopurine (6-me rcaptopurine) because of genetic defects in mercaptopurine inactivation by thiopurine S-methyltransferase. However, mercaptopurine dose intensity, a c ritical factor for outcome in patients deficient in thiopurine S-methyltran sferase, can be maintained by means of thiopurine S-methyltransferase pheno typing or genotyping. Patients with reduced fluorouracil (5-fluorouracil) catabolism are more lik ely to be exposed to severe toxicity. The measurement of dihydropyrimidine dehydrogenase activity in patients cannot be considered fully predictive, a nd the role of dihydropyrimidine dehydrogenase gene variants in this syndro me has yet to be clarified. With regard to irinotecan, patients with Gilbert's syndrome phenotype have reduced inactivation of the active topoisomerase I inhibitor 7-ethyl-10-hyd roxycamptothecin (SN-38) caused by a mutation in the UDP-glucuronosyltransf erase 1A1 gene promoter. This subset of patients is more likely to be expos ed to irinotecan toxicity and could be identified by genotyping for gene pr omoter variants. Finally, the experience with amonafide represents a model for dose individu alisation approaches that use simple phenotypic probes.