Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma

Autor: Hendrik Pels, Uwe Schlegel, Alexander Semmler, Ingo G.H. Schmidt-Wolf, Horst Urbach, Marlies Vogt-Schaden, Katjana Orlopp, Annika Jürgens, Matthias Simon, Michael Linnebank, Axel Glasmacher, Susanna Moskau, Christopher Bangard
Přispěvatelé: University of Zurich, Linnebank, M
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Male
Cancer Research
Lymphoma
medicine.medical_treatment
Pharmacology
Central Nervous System Neoplasms
chemistry.chemical_compound
Methionine
Genotype
1306 Cancer Research
Prospective Studies
biology
Microfilament Proteins
Primary central nervous system lymphoma
Brain
Middle Aged
2728 Neurology (clinical)
Oncology
Basic and Translational Investigations
Methionine sulfoxide reductase
Female
2730 Oncology
Oxidoreductases
medicine.drug
Hydroxymethyl and Formyl Transferases
Antimetabolites
Antineoplastic
Cystathionine beta-Synthase
TRPM Cation Channels
610 Medicine & health
Multienzyme Complexes
medicine
Humans
Methylenetetrahydrofolate Reductase (NADPH2)
Transcobalamins
Chemotherapy
Polymorphism
Genetic
medicine.disease
10040 Clinic for Neurology
Tetrahydrofolate Dehydrogenase
Methotrexate
chemistry
Nucleotide Deaminases
Methionine Sulfoxide Reductases
Methylenetetrahydrofolate reductase
biology.protein
Neurology (clinical)
Transcription Factors
Popis: Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677CT (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298AC (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776CG (chi(2) = 19.73; p0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.
Databáze: OpenAIRE
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