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|Methotrexate in Pediatric Osteosarcoma: Response and Toxicity in Relation to Genetic Polymorphisms and Dihydrofolate Reductase and Reduced Folate Carrier 1 Expression|
|Authors: ||Patiño, A. (Ana)|
Zalacain, M. (Marta)
Marrodan, L. (Lucía)
San-Julian, M. (Mikel)
Sierrasesumaga, L. (Luis)
|Keywords: ||Methotrexate/administration & dosage/adverse effects|
Polymerase Chain Reaction
|Issue Date: ||2009|
|Publisher version: ||http://dx.doi.org/10.1016/j.jpeds.2008.11.030|
|Citation: ||Patiño-García A, Zalacaín M, Marrodán L, San-Julián M, Sierrasesúmaga L. Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. J Pediatr. 2009 May;154(5):688-93.|
To determine the influence of the genotype and the level of expression of different enzymes involved in folate metabolism on the response to and toxicity of high-dose methotrexate treatment in pediatric osteosarcomas.
STUDY DESIGN: DHFR and Reduced folate carrier 1 (RFC1) semiquantitative expression was analyzed in 34 primary and metastatic osteosarcoma tissues by real-time polymerase chain reaction. The following polymorphisms were also analyzed in peripheral blood from 96 children with osteosarcoma and 110 control subjects: C677T, A1298C (MTHFR), G80A (RFC1), A2756G (MTR), C1420T (SHMT), the 28bp-repeat polymorphism, and 1494del6 of the TYMS gene. Treatment toxicity was scored after each cycle according to criteria from the World Health Organization.
RESULTS: DHFR and RFC1 expression was lower in initial osteosarcoma biopsy specimens than in metastases (P = .024 and P = .041, respectively). RFC1 expression was moderately decreased in samples with poor histologic response to preoperative treatment (P = .053). Patients with osteosarcoma with G3/G4 hematologic toxicity were more frequently TT than CT/CC for C677T/MTHFR (P = .023) and GG for A2756G/MTR (P = .048 and P = .057 for gastrointestinal and hematologic toxicity, respectively).
CONCLUSIONS: The role of C677T/MTHFR and A2756G/MTR on chemotherapy-induced toxicity should be further investigated in pediatric osteosarcomas receiving high-dose methotrexate. Altered expression of DHFR and RFC1 is a feasible mechanism by which osteosarcoma cells become resistant to methotrexate.
|Permanent link: ||http://hdl.handle.net/10171/23770|
|Appears in Collections:||DA - CUN - Cirugía ortopédica y traumatología - Artículos de revista|
DA - CUN - Pediatría - Artículos de revista
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