Ragia Georgia, Maslarinou Anthi, Atzemian Natalia, Biziota Eirini, Koukaki Triantafyllia, Ioannou Charalampia, Balgkouranidou Ioanna, Kolios George, Kakolyris Stylianos, Xenidis Nikolaos, Amarantidis Kyriakos, Manolopoulos Vangelis G
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
Individualised Medicine and Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece.
Front Pharmacol. 2023 Sep 14;14:1248898. doi: 10.3389/fphar.2023.1248898. eCollection 2023.
Dihydropyrimidine dehydrogenase (DPD), encoded by gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. variants rs3918290, rs55886062, rs67376798, and rs75017182 are currently included in FP genetic-based dosing guidelines and are recommended for genotyping by the European Medicines Agency (EMA) before treatment initiation. In Greece, however, no data exist on genotyping. The aim of the present study was to analyze prevalence of rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients. Study group consisted of 313 FP-treated cancer patients. genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160). Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity ( = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, = 0.004, 97.9% specificity). deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, = 0.014), neurological (OR: 4.134, = 0.040) and nutrition/metabolism (OR: 4.821, = 0.035) toxicities. FP dose intensity was significantly reduced in deficient patients ( = -0.060, <0.001). rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of ** was associated with grade 3-4 toxicity (OR: 3.725, = 0.007). Our findings confirm the clinical validity of reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment genotyping should be implemented in clinical practice and guide FP dosing. *gene interactions merit further investigation as to their potential to increase the prognostic value of genotyping and improve safety of FP-based chemotherapy.
由基因编码的二氢嘧啶脱氢酶（DPD）是负责氟嘧啶（FP）分解代谢的限速酶。基因变异严重影响DPD活性，并且是FP相关毒性的有效预测指标。变异体rs3918290、rs55886062、rs67376798和rs75017182目前已被纳入基于FP基因的给药指南，欧洲药品管理局（EMA）建议在开始治疗前对其进行基因分型。然而，在希腊，尚无关于基因分型的数据。本研究的目的是分析rs3918290、rs55886062、rs67376798、rs75017182以及另外的rs1801160变异体的流行情况，并评估它们与希腊癌症患者中FP诱导毒性之间的关联。研究组由313例接受FP治疗的癌症患者组成。使用TaqMan分析C__30633851_20（rs3918290）、C__11985548_10（rs55886062）、C__27530948_10（rs67376798）、C_104846637_10（rs75017182）和C__11372171_10（rs1801160）在QuantStudio™12K Flex实时PCR系统（赛默飞世尔科技公司）上进行基因分型。208例患者（66.5%）记录了任何等级的毒性（1 - 4级）。其中，25例患者（12%）经历了3 - 4级毒性。在9例患者（2.9%）中检测到EMA推荐的变异体，所有这些患者均出现毒性（P = 0.031，特异性100%）。在3 - 4级毒性病例中发现该频率增加（12%，P = 0.004，特异性97.9%）。DPD缺陷增加了3 - 4级毒性的几率（OR：6.493，P = 0.014）以及1 - 4级胃肠道毒性（OR：13.990，P = 0.014）、神经毒性（OR：4.134，P = 0.040）和营养/代谢毒性（OR：4.821，P = 0.035）的几率。DPD缺陷患者的FP剂量强度显著降低（P = -0.060，P <0.001）。rs1801160变异体与FP诱导的毒性或剂量强度无关。**的三联相互作用与3 - 4级毒性相关（OR：3.725，P = 0.007）。我们的研究结果证实了DPD功能降低等位基因作为希腊人群中FP相关毒性发生风险因素的临床有效性。治疗前DPD基因分型应在临床实践中实施并指导FP给药。*基因相互作用增加DPD基因分型的预后价值以及改善基于FP的化疗安全性的潜力值得进一步研究。
