The Relationship of Polymorphism of RFC-I Gene on Methotrexate Serum Level and Related Toxicity in Pediatric Acute Lymphoblastic Leukemia

Abstract

Introduction: Methotrexate is one of the most effective agents in chemotherapy regimens for childhood ALL. However, methotrexate has remarkable side effects, which causes complications in various tissues and organs of some patients under treatment of this drug. It is proved that genetic factors can determine methotrexate toxicity. The aim of this study is to evaluate the effect of RFC-I A80G polymorphism on toxicity and serum level of methotrexate in children affected by acute lymphoblastic leukemia. Methods: A80G polymorphism of RFC-I was genotyped with PCR-RFLP method in 69 ALL patients treated with methotrexate. The relation between RFC-I genotypes and serum level of methotrexate and toxicity were evaluated using HPLC method and common terminology criteria for adverse events (CTCAE) respectively. Results: In this study, frequency of allele A for A80G polymorphism was 42.8% in patients who were studied. In consolidation phase, allele A frequency in patients with hepatotoxicity was higher than patients with no hepatic event (P=0.03, OR=2.32, 95% CI=1.10-4.98). Nevertheless, there were not any association between the other types of toxicity and RFC-I genotypes. Also, there was no association between A80G genotypes and the serum level of methotrexate. Conclusion: Based on the obtained results, we concluded that allele A of A80G polymorphism of RFC-I gene is a risk factor for methotrexate hepatotoxicity in consolidation phase and the A80G polymorphism can be utilized for prediction of methotrexate toxicity and dose adjustment.

Preventive Healthcare and Management for Acute Lymphoblastic Leukaemia in Adults: Case Report and Literature Review

“…The strongest predictor of hyperbilirubinemia was the UGT1A1 promoterrepeat polymorphism [61]. The RFC-1 genotype is associated with hepatotoxicity related to methotrexate in the consolidation phase [73]. Genetic polymorphisms in the cytochrome P450 (CYP), glutathione S-transferase (GST), and aldehyde dehydrogenase (ALDH) families of enzymes have been found to impact the response to and/or toxicity associated with cyclophosphamide-based therapies [74].…”