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.
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: Torben S Mikkelsen; Caroline F Thorn; Jun J Yang; Cornelia M Ulrich; Deborah French; Gianluigi Zaza; Henry M Dunnenberger; Sharon Marsh; Howard L McLeod; Kathy Giacomini; Mara L Becker; Roger Gaedigk; James Steven Leeder; Leo Kager; Mary V Relling; William Evans; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-10 Impact factor: 2.089
Authors: Susan M Wernimont; Farbod Raiszadeh; Patrick J Stover; Eric B Rimm; David J Hunter; Wenbo Tang; Patricia A Cassano Journal: J Nutr Date: 2010-12-22 Impact factor: 4.798
Authors: Branden S Moriarity; George M Otto; Eric P Rahrmann; Susan K Rathe; Natalie K Wolf; Madison T Weg; Luke A Manlove; Rebecca S LaRue; Nuri A Temiz; Sam D Molyneux; Kwangmin Choi; Kevin J Holly; Aaron L Sarver; Milcah C Scott; Colleen L Forster; Jaime F Modiano; Chand Khanna; Stephen M Hewitt; Rama Khokha; Yi Yang; Richard Gorlick; Michael A Dyer; David A Largaespada Journal: Nat Genet Date: 2015-05-11 Impact factor: 38.330
Authors: F Aminkeng; C J D Ross; S R Rassekh; L R Brunham; J Sistonen; M-P Dube; M Ibrahim; T B Nyambo; S A Omar; A Froment; J-M Bodo; S Tishkoff; B C Carleton; M R Hayden Journal: Pharmacogenomics J Date: 2013-04-16 Impact factor: 3.550