Boyer Jean-Christophe, Etienne-Grimaldi Marie-Christine, Thomas Fabienne, Quaranta Sylvie, Picard Nicolas, Loriot Marie-Anne, Poncet Delphine, Gagnieu Marie-Claude, Ged Cécile, Broly Franck, Le Morvan Valérie, Bouquié Régis, Gaub Marie-Pierre, Philibert Laurent, Ghiringhelli François, Le Guellec Chantal
CHU Carémeau, unité de toxicologie, laboratoire Biochimie, 4, rue du Professeur Robert-Debré, 30029 Nîmes, France.
Centre Antoine-Lacassagne, Laboratoire d'oncopharmacologie, Nice, France.
Bull Cancer. 2014 Jun;101(6):533-53. doi: 10.1684/bdc.2014.1933.
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.
伊立替康是一种细胞毒性药物，通过静脉输注用于治疗晚期结直肠癌。其抗癌活性源于其生物活化成SN - 38代谢物，该代谢物通过肝脏酶尿苷二磷酸 - 葡萄糖醛酸基转移酶1A1（UGT1A1）的葡萄糖醛酸化作用被清除。在普通人群中，UGT1A1酶活性因UGT1A1基因多态性存在广泛的个体间差异。来自法国国家药物遗传学网络（RNPGx）和临床肿瘤药理学组（GPCO）的联合工作组在此呈现了一篇最新综述，涉及与UGT1A1基因变异相关的疗效和毒性临床研究。通过对该综述的批判性分析清楚地表明，对于高于180mg/m²的剂量，在日常临床实践中，通过在开始治疗前推广使用简单的药物遗传学检测，可以预防伊立替康引起的血液学和消化系统毒性。还从提高治疗疗效的角度讨论了该检测的临床相关性，即对于不携带有害等位基因的患者有可能增加伊立替康剂量。该检测涉及使用血液样本分析UGT1A1基因的启动子区域（UGT1A1*28等位基因）。描述了最佳实施方法、实验室成本以及结果解读，目的是便于在临床常规中开展该分析。法国存在在临床常规中进行此检测的实验室网络，这使得推广UGT1A1缺陷筛查成为可能，从而保证众多接受基于伊立替康治疗的晚期结直肠癌患者能够平等获得安全治疗和优化的基于伊立替康的治疗。
