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
Recent studies point to a role of nuclear factor (NF)-kappaB signaling in a subset of diffuse large B cell lymphomas. We have analyzed the expression of 21 genes encoding NF-kappaB family members, upstream modulators, and targets in 32 primary central nervous system lymphomas (PCNSLs) by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with nonmalignant germinal center centroblasts, expression of BCL10, REL, IAP1, and TRAF1 was significantly lower in PCNSLs, whereas that of BAX, BCLXL, BCL2, MALT1, CARD9, CARD10, CARD11, CARD14, CCND2, cFLIP, RELA, RELB, NFKB1, NFKB2, and IRF4 was higher. Hierarchical clustering of gene expression data revealed two distinct subgroups of PCNSLs, which were characterized by significantly different transcriptional levels, predominantly of BCL10, but also of REL and IAP1. Thus, these quantitative RT-PCR data with expression of genes of the NF-kappaB family as well as NF-kappaB-regulated genes together with immunohistochemical detection of nuclear RELA and REL indicate activation of the NF-kappaB pathway in PCNSLs, which may contribute to their high proliferative activity and the low level of apoptosis.