Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression.

Abstract

OBJECTIVE:

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.

• Authors: Ana Patiño-García, Marta Zalacaín, Lucía Marrodán, Mikel San-Julián, Luis Sierrasesúmaga
• Journal: The Journal of pediatrics (J Pediatr) Vol. 154 Issue 5 Pg. 688-93 (May 2009) ISSN: 1097-6833 [Electronic] United States
• PMID: 19159907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Carrier Proteins
• Folate Receptors, GPI-Anchored
• RNA, Messenger
• Receptors, Cell Surface
• Folic Acid
• Tetrahydrofolate Dehydrogenase
• Methotrexate

Topics

• Adolescent
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects)
• Bone Neoplasms (drug therapy, genetics, mortality)
• Carrier Proteins (genetics, metabolism)
• Case-Control Studies
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Folate Receptors, GPI-Anchored
• Folic Acid (genetics, metabolism)
• Gastrointestinal Diseases (chemically induced)
• Genotype
• Hematologic Diseases (chemically induced)
• Humans
• Kidney Diseases (chemically induced)
• Male
• Methotrexate (administration & dosage, adverse effects)
• Osteosarcoma (drug therapy, genetics, mortality)
• Polymerase Chain Reaction
• Polymorphism, Genetic
• RNA, Messenger (metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Tetrahydrofolate Dehydrogenase (genetics, metabolism)