Abstract
MTHFR is a crucial enzyme in folate metabolism. This study aimed to determine the relationship between MTHFR genetic polymorphism and elimination and toxicities of methotrexate (MTX). To do that, the study enrolled 145 patients diagnosed with acute lymphoblastic leukemia, who received chemotherapy following the Chinese Children’s Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL)-2015 protocol (clinical trial number: ChiCTR-IPR-14005706). We analyzed the effects of MTHFR C677T and A1298C polymorphisms on MTX elimination and toxicities. Patients with the MTHFR C677T TT genotype could tolerate a significantly higher MTX dose than those with the CC/CT genotype. However, patients with C677T TT genotypes had an increased risk of hypokalemia (1.369 to CC and 1.409 to CT types). The MTX infusion rate in patients with the MTHFR A1298C AC genotype was slightly lower than that in those with CC or AA genotypes. Patients with the A1298C AA genotype had a 1.405-fold higher risk of hepatotoxicity than those with the AC genotype (P > 0.05). There was no significant difference between the prevalence of other toxicities among MTHFR C677T or A1298C genotypes (P > 0.05). Neither MTHFR C677T nor A1298C polymorphisms were significantly associated with delayed MTX clearance. To conclude, MTHFR polymorphisms were not good predictors of MTX-related toxicities.
Highlights
Methotrexate (MTX) is a crucial agent in treating pediatric acute lymphoblastic leukemia (ALL)
High-dose methotrexate (HD-MTX) chemotherapy is defined as MTX >500 mg/m2 and is part of the regimen for pediatric ALL [1,2]
In this pharmacogenetic study, we investigated the relationship between Methylenetetrahydrofolate reductase (MTHFR) C677T or MTHFR A1298C polymorphisms and the elimination and toxicities of MTX in Chinese children suffering from ALL
Summary
Methotrexate (MTX) is a crucial agent in treating pediatric acute lymphoblastic leukemia (ALL). Upon entering cells through the reduced folate carrier, MTX competitively inhibits dihydrofolate reductase, which leads to reduced conversion of dihydrofolate to tetrahydrofolate. A deficiency of tetrahydrofolate inhibits the synthesis of DNA, RNA, and protein and exerts the antitumor effect of MTX [2,3] (Figure 1). High-dose methotrexate (HD-MTX) chemotherapy is defined as MTX >500 mg/m2 and is part of the regimen for pediatric ALL [1,2]. High-intensity chemotherapy can improve the overall prognosis of childhood ALL, but can cause severe toxicities. MTX-induced toxicities are a major cause of treatment interruption and lead to an enhanced risk of relapse and even death [4]
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