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

Jeong A Park, Hee Young Shin, Jeong A Park, Hee Young Shin

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.

Keywords: Methotrexate; Osteosarcoma; Pediatric; Single nucleotide polymorphism; Toxicity.

Conflict of interest statement

Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

Figures

Fig. 1. Plasma methotrexate levels at 48…
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).
Fig. 2. Plasma methotrexate levels at 48…
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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