title: [Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan].
abstract: Irinotecan is a cytotoxic agent administered by IV infusion in the treatment of advanced colorectal cancer. Its anticancer activity results from its bioactivation into SN-38 metabolite, which is cleared through glucuronidation by the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). In the general population, there is wide inter-subject variability in UGT1A1 enzyme activity related to UGT1A1 gene polymorphisms. The French joint workgroup coming from the National Pharmacogenetic Network (RNPGx) and the Group of Clinical Oncologic Pharmacology (GPCO) herein presents an updated review dealing with efficacy and toxicity clinical studies related to UGT1A1 genetic variants. From a critical analysis of this review it clearly emerges that, for doses higher than 180 mg/m(2), hematologic and digestive irinotecan-induced toxicities could be prevented in daily clinical practice by generalizing the use of a simple pharmacogenetic test before starting treatment. The clinical relevance of this test is also discussed in terms of treatment efficacy improvement, with the possibility of increasing the irinotecan dose in patients not bearing the deleterious allele. This test involves using a blood sample to analyze the promoter region of the UGT1A1 gene (UGT1A1*28 allele). Best execution practices, laboratory costs, as well as results interpretation are described with the aim of facilitating the implementation of this analysis in clinical routine. The existence of a French laboratories network performing this test in clinical routine makes it possible to generalize UGT1A1 deficiency screening, so as to guarantee equal access to safe treatment and optimized irinorecan-based therapy for the many patients receiving irinotecan-based therapy in advanced colorectal cancer.
authors: CHU Carémeau, unité de toxicologie, laboratoire Biochimie, 4, rue du Professeur Robert-Debré, 30029 Nîmes, France.
authors: Jean-Christophe
authors: JC
authors: Boyer
authors: Centre Antoine-Lacassagne, Laboratoire d'oncopharmacologie, Nice, France.
authors: Marie-Christine
authors: MC
authors: Etienne-Grimaldi
authors: Institut Claudius-Regaud, Laboratoire de pharmacologie, Toulouse, France.
authors: Fabienne
authors: F
authors: Thomas
authors: CHU Timone, LBM, service de pharmacocinétique/toxicologie et hématologie, Marseille, France.
authors: Sylvie
authors: S
authors: Quaranta
authors: CHU Dupuytren, service de pharmacologie, toxicologie et pharmacovigilance, Limoges, France.
authors: Nicolas
authors: N
authors: Picard
authors: Hôpital européen George-Pompidou, laboratoire de biochimie, UF pharmacogénétique et oncologie moléculaire, Paris, France.
authors: Marie-Anne
authors: MA
authors: Loriot
authors: UMOMT Centre de biologie Sud, service de biochimie, Lyon, France.
authors: Delphine
authors: D
authors: Poncet
authors: CHU Edouard-Herriot, UF de pharmacologie spécialisée, laboratoire de biochimie et biologie moléculaire, Lyon, France.
authors: Marie-Claude
authors: MC
authors: Gagnieu
authors: CHU Pellegrin, pôle de biologie et pathologie, Laboratoire du Pr Hubert-de-Verneuil, Bordeaux, France.
authors: Cécile
authors: C
authors: Ged
authors: CHRU Lille, centre de biologie et pathologie, Unité de génopathies et de pharmaco/toxicogénétique, Lille, France.
authors: Franck
authors: F
authors: Broly
authors: Institut Bergonié, département de biologie médicale, Bordeaux, France.
authors: Valérie
authors: V
authors: Le Morvan
authors: CHU Nantes, institut de biologie, laboratoire de pharmacologie et toxicologie, Nantes, France.
authors: Régis
authors: R
authors: Bouquié
authors: CHU Hautepierre, Laboratoire de biochimie et biologie moléculaire, Strasbourg, France.
authors: Marie-Pierre
authors: MP
authors: Gaub
authors: Institut du cancer, laboratoire d'oncopharmacologie, Montpellier, France.
authors: Laurent
authors: L
authors: Philibert
authors: Centre Georges-François-Leclerc, laboratoire de biopathologie, Dijon, France.
authors: François
authors: F
authors: Ghiringhelli
authors: CHU Bretonneau, unité de pharmacogénétique, Laboratoire de biochimie biologie moléculaire, Tours, France.
authors: Chantal
authors: C
authors: Le Guellec
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D044466:Asian People; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D005602:France; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005838:Genotype; D005878:Gilbert Disease / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D060735:Pharmacovigilance; D010641:Phenotype; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D014481:United States; D044465:White People; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme
keywords: UGT1A1; colorectal cancer; irinotecan; pharmacogenetics