Assuntos
Tomada de Decisão Clínica/métodos , Marcadores Genéticos/genética , Metotrexato/uso terapêutico , Farmacogenética/métodos , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Marcadores Genéticos/efeitos dos fármacos , Humanos , Metotrexato/efeitos adversosRESUMO
Methotrexate (MTX), a structural analog of folic acid, is widely employed in the treatment of different cancers and autoimmune diseases. Despite the successful results observed, the main disadvantage lies in interpatient variability in the pharmacokinetic and pharmacodynamic parameters. In particular, adverse events and toxicities induced by MTX are a matter of concern and can be the cause of dose reduction or treatment discontinuation. Among the different approaches to reduce MTX therapeutic limitations, pharmacogenomics contributes by considering the effect of inherited genetic differences on those parameters. This review provides an update on MTX pharmacogenomics. It reports the contribution of main gene polymorphisms involved in the influx, efflux, cellular effect, and elimination on MTX toxicity and efficacy, on all the diseases treated with this drug. From the analysis of the data presented in this review, we concluded that only gene polymorphisms MTHFR rs1801133, SLC19A1 rs1051266, and TYMS rs34743033 could influence clinical decision-making.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Imunossupressores/efeitos adversos , Metotrexato/efeitos adversos , Farmacogenética/métodos , Variantes Farmacogenômicos , Polimorfismo Genético , Medicina de Precisão/métodos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Tomada de Decisão Clínica , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Seleção de Pacientes , Testes Farmacogenômicos , Valor Preditivo dos Testes , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Medição de Risco , Timidilato Sintase/genética , Timidilato Sintase/metabolismoRESUMO
BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.
