Association of CYP3A5 Expression and Vincristine Neurotoxicity in Pediatric Malignancies in Turkish Population

Abstract

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 CYP3A5*3/*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.