Farmacogénetica del metotrexato en pacientes pediátricos con leucemia linfoblástica aguda

Abstract

ABSTRACT: Background. Methotrexate (MTX) is a key compound of chemoterapeutic regimens used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Resistence and toxicity, may hamper the efficacy of this treatment. Methylenetetrahydrofolate reductase (MTHHR) has a major impact on the regulation of the folic acid patway due to conversion of 5,10- methylenetetrahydrofolate (methylene-THF) to 5-methyl- THF. The C677T polymorphism have been show to reduce anzyme activity and were associated with MTX resistence in ALL. RFC1 a major route for the transport of folates in cells. The RFC1 G80A polymorphisms have been reported that patients with the A80 variant had a worse outcome. We investigated whether reduced folate carrier 1 (RFC1) G80A or methylenetetrahydrofolate reductase (MTHHR) C677T polymorphisms were associated with MTX plasma levels and childhood ALL outcome. Methods. Genomic DNA of 81 children (1-19 years old) was genotyped to identify polymorphisms at MTHFR C677T and RFC1 G80A. The clinical records were reviewed retrospectively. Association between MTX plasma levels, mucositis and relapse and polymorphisms were studied by multiple logistic regression Results. No significant associations between genotypes MTHFR C677T, RFC1 G80A and methotrexate plasma levels and relapse were observed. Patients with RFC1 GA and RFC1 AA were associated with “protection” to develop mucositis (OR=0.23, CI 95% =0.056-0.98) and (OR=0.15, CI95%= 0.029-0.77) respectively. Patients with MTHFR CC genotype had an increased risk to develop mucositis (OR=6.66, CI95%=1.29-34.25). Conclution. This study suggest that MTHHR C677T and RFC1 G80A polymorphisms may serve as predictors of toxicity.

RESUMEN: El Metotrexato (MTX) es un componente clave de los regímenes de quimioterapia usado en el tratamiento de niños con Leucemia Linfoblastica Aguda (LLA). Resistencia y toxicidad, puede dificultar la eficacia del tratamiento. La enzima Metilentetrahidrofolato Reductasa (MTHFR) tiene un gran impacto sobre la regulación del ciclo del ácido fólico, cataliza la conversión de 5,10-metilentetrahidrofolato (metilen-THF) a 5-metil-THF. El polimorfismo C677T ha sido demostrado que reduce la actividad enzimática y fue asociado con Resistencia a MTX en LLA. RFC1 es el principal transportador de folatos al interior de la célula. El polimorfismo G80A del gen RFC1 ha sido reportado que pacientes con la variante A80 tienen un mal pronóstico. Nosotros investigamos si el polimorfismo del transportador de folatos reducido (RFC1) G80A o de la metiltetrahidrofolato reducido (MTHFR) C677T están asociados con niveles de MTX en plasma y el resultado de pacientes pediátricos con LLA.