Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma.
- Author:
Jeong A PARK
1
;
Hee Young SHIN
Author Information
- Publication Type:Original Article
- Keywords: Pediatric; Osteosarcoma; Methotrexate; Toxicity; Single nucleotide polymorphism
- MeSH: Folic Acid*; Humans; Metabolism; Methotrexate*; Mucositis; Osteosarcoma*; Plasma; Polymorphism, Genetic*; Polymorphism, Single Nucleotide
- From:Blood Research 2016;51(1):50-57
- CountryRepublic of Korea
- Language:English
- 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.
