Kayilioğlu Hülya, Kocak Ulker, Kan Karaer Derya, Percin Emriye F, Sal Ertan, Tekkesin Funda, Isik Melek, Oner Nergiz, Belen Fatma B, Yilmaz Keskin Ebru, Okur Arzu, Albayrak Meryem, Kaya Zuhre, Pinarli Faruk G, Yenicesu Idil, Karadeniz Ceyda, Oguz Aynur, Gursel Turkiz
*Department of Pediatric Hematology and Oncology †Department of Genetics, Gazi University School of Medicine ‡Department of Pediatric Hematology and Oncology, Kirikkale University School of Medicine, Ankara, Turkey.
J Pediatr Hematol Oncol. 2017 Aug;39(6):458-462. doi: 10.1097/MPH.0000000000000910.
Vincristine is a widely used chemotherapeutic agent in the treatment of childhood malignancies. Neuropathy is the most common adverse effect. CYP3A4 and CYP3A5 enzymes of cytochrome p450 enzyme system are responsible in vincristine metabolism. Genetic polymorphism may alter the vincristine metabolism and the neurotoxicity rate. In this study, distribution of CYP3A5 alleles among Turkish children with malignancies, relation between CYP3A5 genotype and neurotoxicity rates, as well as severity and duration of neuropathy and total vincristine doses were investigated. Patient group consisted of 115 patients (age, 1 to 17 y) with acute lymphoblastic leukemia and solid tumors, who were treated with vincristine consisting chemotherapy protocols. Control group consisted of 50 children without any neurological symptom or disorders. All patient files were reviewed for presence and severeness of neurotoxicity symptoms. Blood samples were obtained and CYP3A5 genotypes were analyzed. Neurotoxicity occurred in 20.8% of patients. Although it was found to occur more frequently after 4 doses of vincristine, and rates were higher in the low-dose vincristine group suggesting other contributing factors. Although neurotoxicity rate in the CYP3A5*1/3 genotype was 17.6%, it was 21.6% in the CYP3A53/*3 genotype and the difference was not statistically significant (P<0.05). This study suggested that vincristine-related neurotoxicity is dose-independent and genotype is not the only causative factor in the occurrence of neurotoxicity in these patients.
长春新碱是治疗儿童恶性肿瘤广泛使用的化疗药物。神经病变是最常见的不良反应。细胞色素P450酶系统的CYP3A4和CYP3A5酶负责长春新碱的代谢。基因多态性可能改变长春新碱的代谢及神经毒性发生率。本研究调查了土耳其恶性肿瘤儿童中CYP3A5等位基因的分布、CYP3A5基因型与神经毒性发生率的关系，以及神经病变的严重程度、持续时间和长春新碱的总剂量。患者组由115例（年龄1至17岁）急性淋巴细胞白血病和实体瘤患者组成，他们接受了含长春新碱的化疗方案治疗。对照组由50名无任何神经症状或疾病的儿童组成。审查了所有患者档案中神经毒性症状的存在情况和严重程度。采集血样并分析CYP3A5基因型。20.8%的患者发生了神经毒性。虽然发现神经毒性在4剂长春新碱后更频繁发生，且低剂量长春新碱组的发生率更高，提示存在其他影响因素。虽然CYP3A5*1/3基因型的神经毒性发生率为17.6%，但CYP3A53/*3基因型为21.6%，差异无统计学意义（P<0.05）。本研究提示，长春新碱相关神经毒性与剂量无关，基因型并非这些患者发生神经毒性的唯一致病因素。
