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Pharmacogenetic pol...
Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
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- Gregers, Jannie (författare)
- Linköpings universitet,Klinisk farmakologi,Hälsouniversitetet
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- Jarle Christensen, Ib (författare)
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark
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- Dalhoff, Kim (författare)
- Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
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- Schroeder, Henrik (författare)
- Department of Pediatric, the University Hospital in Skejby, Aarhus, Denmark
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- Carlsen, Niels (författare)
- Department of Pediatric, the University Hospital in Odense, Denmark
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- Rosthoej, Steen (författare)
- Department of Pediatric, the University Hospital in Aalborg, Denmark
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- Lausen, Birgitte (författare)
- Department of Pediatric, Rigshospitalet, the University Hospital in Copenhagen, Denmark
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- Schmiegelow, Kjeld (författare)
- Institute of Gynecology, Obstetrics, and Pediatrics, The Medical Faculty, University of Copenhagen, Denmark
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- Peterson, Curt (författare)
- Östergötlands Läns Landsting,Linköpings universitet,Klinisk farmakologi,Hälsouniversitetet,Onkologiska kliniken US
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(creator_code:org_t)
- 2012
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001). In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.
Nyckelord
- MEDICINE
- MEDICIN
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