Evaluating Methotrexate Toxicity and Its Association with ABCB1 Genetic Polymorphism in Children with Acute Lymphoblastic Leukemia

Abstract

Background: Acute lymphoblastic leukemia (ALL) is among the most prevalent type of hematologic malignancy in children. The Children’s Oncology Group protocol recognizes methotrexate (MTX) as a therapy for this problem in children, despite its several complications. The relationship between MTX toxicity and ATP-binding cassette subfamily B member 1 (ABCB1) SNPs in ALL children patients has been investigated in many studies. Objectives: Regarding the controversial findings reported by these studies, the present work aims to evaluate Methotrexate toxicity and its association with ABCB1 Genetic Polymorphism in ALL pediatric patients. Methods: Blood samples were collected from pediatric ALL patients. Next, DNA was extracted and polymerase chain reaction (PCR) was conducted using 300 μMol/μL of direct primers in 50 µL as the ultimate volume. ABCB1 gene was amplified using the PCR technique, and 0.5% agarose gel electrophoresis was used to identify reaction products. Afterward, the PCR fragments’ length was proved by observing through UV-transilluminator. Finally, liver and blood toxicity was studied in all cases under treatment with MTX. Results: In the present study, 81 children with ALL (36 females and 45 males) with a mean age of 6.32 ± 3.08 years old were examined. The ABCB1 1199 G->A gene mutation frequency and the ABCB1 3435 C->T gene mutation frequency was 4.9 and 70.4%, respectively. The results showed no statistically significant difference between leukopenia, gastrointestinal toxicity, renal toxicity, hepatotoxicity, anemia, thrombocytopenia, and neutropenia in cases having homozygous heterozygous ABCB1 3435 C->T and ABCB1 1199 G->A mutant polymorphisms than those having ordinary polymorphism. Conclusions: Overall, it seems that C3435 T, G1199A, and ABCB1 are not significant MTX toxicity markers in pediatric ALL cases.

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“…While some studies have associated the 3435T allele or TT genotype with decreased P-gp expression and increased drug levels, others have linked this genotype to the increased expression of P-gp or no genotypic effect at all [ 204 , 308 , 313 , 314 , 315 , 316 , 317 ]. Similarly, the 3435 CC genotype was associated with increased drug concentrations or no genetic effect on the plasma drug concentrations [ 300 , 318 , 319 , 320 , 321 , 322 , 323 , 324 ]. In addition, a recent study did not find a significant association between SNP C435T and the pathogenesis of colorectal cancer.…”