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Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in

Jeong A Park1, Hee Young Shin2

  • 1Department of Pediatrics, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.

Blood Research
|April 23, 2016
PubMed
Abstract

Insights

Genetic variations in methotrexate metabolism influence drug levels and toxicity in pediatric osteosarcoma patients. Understanding these polymorphisms can help predict and manage adverse effects during treatment.

Area of Science:

  • Pharmacogenomics
  • Pediatric Oncology
  • Drug Metabolism

Background:

  • Methotrexate (MTX) is a key chemotherapy agent for osteosarcoma, acting as a folic acid antagonist.
  • Individual responses to MTX vary, potentially due to genetic differences in drug-metabolizing enzymes.
  • Investigating these genetic factors is crucial for optimizing treatment in pediatric patients.

Purpose of the Study:

  • To examine the relationship between specific genetic polymorphisms and plasma methotrexate concentrations.
  • To assess the correlation between MTX levels, genetic variations, and treatment-induced toxicities in pediatric osteosarcoma.
  • To identify genetic markers that may predict MTX toxicity.

Main Methods:

  • Analyzed 4 single nucleotide polymorphisms (SNPs) in ATIC, MTHFR, and SLC19A1 genes from 37 pediatric osteosarcoma patients.
  • Measured serial plasma MTX concentrations following high-dose MTX therapy.
  • Evaluated MTX-induced toxicities, including mucositis and renal toxicity, and correlated them with genetic data and MTX levels.

Main Results:

  • The SLC19A1 80G>A polymorphism was significantly associated with plasma MTX levels at 48 hours post-infusion (P=0.031).
  • Elevated MTX plasma concentrations correlated with increased risk of mucositis (at 48h, P=0.007) and renal toxicity (at 72h, P=0.002).
  • The SLC19A1 gene SNP was linked to the development of severe mucositis (P=0.026).

Conclusions:

  • Plasma MTX levels are linked to gastrointestinal and renal toxicities in pediatric osteosarcoma patients.
  • Genetic polymorphisms affecting MTX metabolism may influence drug concentrations.
  • These genetic variations could play a role in the development of significant side effects during high-dose MTX therapy.
Keywords:
MethotrexateOsteosarcomaPediatricSingle nucleotide polymorphismToxicity

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