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. 2016 Mar;51(1):50-7.
doi: 10.5045/br.2016.51.1.50. Epub 2016 Mar 25.

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

Jeong A Park  1 , Hee Young Shin  2
Affiliations

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

Jeong A Park et al. Blood Res. 2016 Mar.

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.

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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
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
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.
See this image and copyright information in PMC

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References

    1. Relling MV, Fairclough D, Ayers D, et al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol. 1994;12:1667–1672. - PubMed
    1. Rask C, Albertioni F, Bentzen SM, Schroeder H, Peterson C. Clinical and pharmacokinetic risk factors for high-dose methotrexate-induced toxicity in children with acute lymphoblastic leukemia-a logistic regression analysis. Acta Oncol. 1998;37:277–284. - PubMed
    1. Johansson ÅM, Hill N, Perisoglou M, Whelan J, Karlsson MO, Standing JF. A population pharmacokinetic/pharmacodynamic model of methotrexate and mucositis scores in osteosarcoma. Ther Drug Monit. 2011;33:711–718. - PubMed
    1. de Jonge R, Tissing WJ, Hooijberg JH, et al. Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood. 2009;113:2284–2289. - PubMed
    1. Gorlick R, Goker E, Trippett T, Waltham M, Banerjee D, Bertino JR. Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med. 1996;335:1041–1048. - PubMed