Oncologie

, Volume 16, Issue 2–3, pp 103–111 | Cite as

Impact du génotype sur la tolérance à l’irinotécan et au cisplatine

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Résumé

L’irinotécan et le cisplatine sont deux médicaments anticancéreux dont les effets indésirables fréquents et sévères — toxicité hématologique et digestive pour l’irinotécan, ototoxicité pour le cisplatine — présentent une importante variabilité interindividuelle d’origine en partie génétique. Différentes études ont été mises en place pour identifier les déterminants génétiques de ces toxicités afin de prédire le risque de survenue d’effets indésirables et adapter le traitement en fonction du niveau de risque. Pour l’irinotécan, des recommandations de dose commencent à émerger des nombreux travaux réalisés sur les polymorphismes de l’UDP-glucuronosyl-transférase 1A1 (UGT1A1), principale enzyme impliquée dans la détoxification du métabolite actif de l’irinotécan, le SN-38. La découverte récente du rôle d’autres enzymes (notamment de la même sous-famille UGT1A) et transporteurs (en particulier de la superfamille ABC, ATP Binding Cassette) intervenant dans la pharmacocinétique de l’irinotécan risque de complexifier l’élaboration de telles recommandations. Pour le cisplatine, la détermination des gènes d’intérêt est encore en cours, car les résultats des différentes études restent controversés. Plusieurs gènes impliqués dans les processus intracellulaires de l’ototoxicité ont été évoqués, tels que les gènes des glutathions Stransférases (GST), de la mégaline, de la thiopurine méthyltransférase (TPMT), de la catéchol O-méthyltransférase (COMT) et du transporteur ABCC3, ces trois derniers ayant été intégrés dans un modèle de prédiction de l’ototoxicité. Pour l’irinotécan comme pour le cisplatine, des études complémentaires sont donc encore nécessaires pour atteindre une individualisation complète du traitement.

Mots clés

Irinotécan SN-38 Cisplatine Pharmacogénétique Polymorphismes 

Impact of Genotype on Irinotecan and Cisplatin’s Safety

Abstract

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.

Keywords

Irinotecan SN-38 Cisplatin Pharmacogenetics Polymorphisms 

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Copyright information

© Springer-Verlag France 2014

Authors and Affiliations

  1. 1.EA4553 Institut Claudius-RegaudUniversité de ToulouseToulouseFrance

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