RESUMO
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.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), 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.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Metionina/metabolismo , Metotrexato/efeitos adversos , Polimorfismo Genético/genética , Encéfalo/metabolismo , Cistationina beta-Sintase/genética , Feminino , Humanos , Hidroximetil e Formil Transferases/genética , Masculino , Metionina Sulfóxido Redutases , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Nucleotídeo Desaminases/genética , Oxirredutases/genética , Estudos Prospectivos , Canais de Cátion TRPM/genética , Tetra-Hidrofolato Desidrogenase/genética , Transcobalaminas/genética , Fatores de Transcrição/genéticaRESUMO
Prompted by the worldwide surge in fungal infections, the past decade has witnessed a considerable expansion in antifungal drug research. New compounds have entered the clinical arena, and major progress has been made in defining paradigms of antifungal therapies. This article provides an up-to-date review on the clinical pharmacology, indications, and dosage recommendations of approved and currently investigational therapeutics for treatment of invasive fungal infections in adult and pediatric patients.