Blood Res.  2016 Mar;51(1):50-57. 10.5045/br.2016.51.1.50.

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

• Park JA
• Shin HY

• KMID: 2172745
• DOI: http://doi.org/10.5045/br.2016.51.1.50

Abstract

BACKGROUND
Methotrexate (MTX), one of the main drugs used to treat osteosarcoma, is a representative folic acid antagonist. Polymorphisms of various enzymes involved in the metabolism of MTX could contribute to differences in response to MTX in pediatric osteosarcoma patients.
METHODS
Blood and tissue samples were obtained from 37 pediatric osteosarcoma patients who were treated with high-dose MTX therapy. The following 4 single nucleotide polymorphisms (SNPs) were analyzed: ATIC 347C>G, MTHFR 677C>T, MTHFR 1298A>C and SLC19A1 80G>A. Serial plasma MTX concentrations after high-dose MTX therapy and MTX-induced toxicities were evaluated. Correlations among polymorphisms, MTX concentrations and treatment-induced toxicities were assessed.
RESULTS
Plasma MTX levels at 48 hours after high-dose MTX infusion were significantly associated with SLC19A1 80G>A (P=0.031). Higher plasma levels of MTX at 48 and 72 hours were significantly associated with MTX-induced mucositis (P=0.007 and P=0.046) and renal toxicity (P=0.002), respectively. SNP of SLC19A1 gene was associated with development of severe mucositis (P=0.026).
CONCLUSION
This study suggests that plasma levels of MTX are associated with GI and renal toxicities after high-dose MTX therapy, and genetic polymorphisms that affect the metabolism of MTX may influence drug concentrations and development of significant side effects in pediatric patients treated with high-dose MTX.

Keyword

Pediatric; Osteosarcoma; Methotrexate; Toxicity; Single nucleotide polymorphism

MeSH Terms

Folic Acid*
Humans
Metabolism
Methotrexate*
Mucositis
Osteosarcoma*
Plasma
Polymorphism, Genetic*
Polymorphism, Single Nucleotide
Folic Acid
Methotrexate

Figure

• 

  Fig. 1 Plasma methotrexate levels at 48 hours after high-dose methotrexate infusion were significantly associated with the 80G>A variants of SLC19A1 (P=0.03).

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  Fig. 2 Plasma methotrexate levels at 48 (A, B) and 72 hours (C, D) after high-dose methotrexate infusion were significantly associated with a development of grade 3 and 4 of mucositis and kidney toxicity.

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