RESUMO
Subacute methotrexate neurotoxicity (MTX-NT) may occur days to weeks after systemic or intrathecal (IT) MTX administration and is often manifest by stroke-like symptoms. The pathogenesis of MTX-NT has mainly been associated with cerebral folate homeostasis, but the specific mechanism leading to the development of this complication is mostly unknown and is likely to be multifactorial. Most of studies aimed to determine putative genetic determinants of this syndrome have been focused on the methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP). However, there are other functional polymorphisms that have also been identified in enzymes and transporters related to MTX and folate homeostasis. In this context, we carried out an extensive genetic analysis through the screening of 21 SNPs in 11 relevant genes in a five-year-old girl with acute lymphoblastic leukemia (ALL) who developed MTX-NT. The analysis revealed the presence of numerous genetic variants that may have accounted for the neurotoxicity observed. We discuss the putative role of MTX pharmacogenetics in the pathogenesis of MTX-NT.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Ácido Fólico/metabolismo , Metotrexato/efeitos adversos , Síndromes Neurotóxicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Pré-Escolar , Feminino , Ácido Fólico/genética , Humanos , Imageamento por Ressonância Magnética , Metotrexato/uso terapêutico , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismoRESUMO
AIMS: To detect differences in the frequency of the known nonsynonymous CYP2W1 polymorphisms between colorectal cancer patients and healthy subjects. MATERIALS & METHODS: The study group consisted of 150 colorectal patients and 263 controls. The presence of five nonsynonymous CYP2W1 polymorphisms was analyzed by novel amplification-restriction methods. RESULTS: Two nonsynonymous SNPs causing the amino acid substitutions Val432Ile and Gln482His were monomorphic in the population study. Two nonsynonymous SNPs previously unknown in Caucasians, 1463T (rs3808348) and 173C (no rs number assigned), were detected in the population study, although these were not associated with colorectal cancer risk. Regarding the 541G/A polymorphism (rs3735684), the 541G allele (odds ratio: 2.2; 95% CI: 1.2-4.1) and the 541GG genotype (odds ratio: 2.06; 95% CI: 1.1-3.9) were associated with increased colorectal cancer risk in the population studied. Conversely, the 173C-541A-1463C haplotype (odds ratio: 0.46; 95% CI: 0.2-0.9) showed a protective odds ratio value. CONCLUSION: CYP2W1 variant alleles are common among Caucasian individuals and, of these, the CYP2W1 G541A (Ala181Thr) polymorphism is associated with increased colorectal cancer risk.
