RESUMEN
Cancer is the leading cause of disease-related death among children. Vincristine (VCR), a key component of childhood cancer treatment protocols, is associated with the risk of peripheral neuropathy (PN), a condition that may be reversible upon drug discontinuation but can also leave lasting sequelae. Single nucleotide polymorphism (SNP) in genes involved in VCR pharmacokinetics and pharmacodynamics have been investigated in relation to an increased risk of PN. However, the results of these studies have been inconsistent. A retrospective cohort study was conducted to investigate the potential association of drug transporter genes from the ATP-binding cassette (ABC) family and the centrosomal protein 72 (CEP72) gene with the development of PN in 88 Caucasian children diagnosed with cancer and treated with VCR. Genotyping was performed using real-time PCR techniques for the following SNPs: ABCB1 rs1128503, ABCC1 rs246240, ABCC2 rs717620, and CEP72 rs924607. The results indicated that age at diagnosis (OR = 1.33; 95% CI = 1.07-1.75) and the ABCC1 rs246240 G allele (OR = 12.48; 95% CI = 2.26-100.42) were associated with vincristine-induced peripheral neuropathy (VIPN). No association was found between this toxicity and CEP72 rs924607. Our study provides insights that may contribute to optimizing childhood cancer therapy in the future by predicting the risk of VIPN.
Asunto(s)
Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Neoplasias , Enfermedades del Sistema Nervioso Periférico , Polimorfismo de Nucleótido Simple , Medicina de Precisión , Vincristina , Humanos , Vincristina/efectos adversos , Vincristina/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/genética , Niño , Femenino , Masculino , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Preescolar , Medicina de Precisión/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Adolescente , Estudios Retrospectivos , Proteínas de Ciclo Celular/genética , Lactante , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Predisposición Genética a la Enfermedad , Genotipo , Alelos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Proteínas Asociadas a MicrotúbulosRESUMEN
Una paciente pediátrica de 6 años, diagnosticada de leucemia linfoblástica aguda (LLA) de riesgo intermedio, presenta milotoxicidad grave y múltiples infecciones durante la fase de inducción IB del tratamiento con 6-mercaptopurina (6-MP). En las siguientes fases del protocolo de tratamiento, que incluía también 6-MP, la paciente continúa mostrando aplasia de médula ósea y neutropenia, requiriendo numerosos ajustes de dosis e interrupciones. La dosis recomendada de 6-MP se reduce entonces al 5 %. El análisis farmacogenético, realizado en la fase de inducción IB, detectó tres polimorfismos de nucleótido único (SNPs) en el gen que codifica para la enzima tiopurina S-metiltransferasa (TPMT), observándose un fenotipo de metabolizador normal para esta enzima. Como consecuencia, se requirió de un segundo análisis farmacogenético más completo, que reveló polimorfismos patológicos en el gen de la hidrolasa Nudix 15 (NUDT15), explicaría la mielotoxicidad observada en esta paciente. Por ello, un análisis farmacogenético completo debería llevarse a cabo con anterioridad al inicio de 6-MP y de manera rutinaria en la práctica clínica, para conseguir prevenir los efectos adversos graves y/o el fracaso terapéutico. (AU)
A 6-year-old girl diagnosed with intermediate-risk acute lymphoblastic leukemia (ALL) presented with severe my-elotoxicity and multiple infections during phase IB induction treatment with 6-mercaptopurine (6-MP). In the sub-sequent treatment phases, which included 6-MP, the patient continued to show bone marrow aplasia and neu-tropenia, necessitating numerous dose adjustments and interruptions. The recommended dose was eventually reduced to 5 %. A pharmacogenetic analysis, conducted in induction phase IB, detected three single-nucleotide polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene, and the phenotype of a normal metab-olizer was observed. As a result of a second pharmacogenetic analysis, pathological polymorphisms were revealed in Nudix hydrolase 15 (NUDT15), which may explain the patients myelotoxicity. Hence, a pharmacogenetic analysis performed in advance would have been able to prevent her from suffering severe toxicity and/or treatment failure. (AU)