Impact of Genotype on Irinotecan and Cisplatin's Safety

Irinotecan and cisplatin are two chemotherapeutic agents whose frequent and serious adverse effects - haematological and gastrointestinal toxicity for irinotecan, ototoxicity for cisplatine - show wide and partly genetic-based interindividual variability. Several studies have been undertaken to identify genetic variants responsible of these toxicities in order to predict the risk for patients to suffer from them and to adapt treatment to risk levels. Concerning irinotecan, dosing recommendations are about to emerge from many UDP-glucuronosyl-transferase 1A1 (UGT1A1, main enzyme inactivating the active metabolite of irinotecan SN-38) polymorphism-related studies. The development of such recommendations may be complicated by the recent discovery of the role of other enzymes (from the same UGT1A subfamily) and carriers (particularly ATP-binding cassette (ABC) superfamily) involved in irinotecan's pharmacokinetics. For cisplatin, identifying candidate genes is still ongoing because of controversies about different studies' results. Several genes involved in intracellular processes of ototoxicity were discussed, such as the Glutathione S-transferases (GST), megalin, thiopurine methyltransferase (TPMT), catechol O-methyltransferase (COMT) and ABCC3 genes. The last three genes have recently been incorporated in a predictive model of ototoxicity. For both drugs, further studies are still needed to reach a complete individualization of treatment.