Acute lymphoblastic leukemia (ALL) is one of the most frequent oncological disorders in pediatric populations. To date, the drug of choice for the treatment of ALL is methotrexate, a drug associated with a high risk of adverse reactions (ADRs). The xanthine oxidase (A total of 35 Mexican children from Centro Estatal de Cancerología-Durango, Mexico, with ALL and the previously noted polymorphisms as determined qPCR were studied. At the same time, a 12-month drug monitoring program was conducted in accordance with WHO-PAHO guidelines for pharmacovigilance.TheSNPs

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

RESUMENAntecedentes: La leucemia linfoblástica aguda (LLA) es un padecimiento oncológico importante en la población pediátrica mexicana, cuya base genética pudiera modificar la efectividad de la quimioterapia del antifolato metotrexato (MTX) y el tiempo de sobrevida libre de enfermedad y la sobrevida total. Objetivo: Determinar la asociación de 10 polimorfismos genéticos de la vía del folato: en transportadores celulares (COL18A1, SLC19A1, ABCB1 y ABCC5) y las enzimas folilpoliglutamil sintetasa (FPGS) y xantina oxidasa (XO), con la sobrevida de los niños con leucemia linfoblástica aguda. Métodos: En el Centro Estatal de Cancerología de Durango-México, se estudiaron 39 niños con leucemia linfoblástica aguda tratados con MTX y 102 controles sin la enfermedad, a quienes mediante qPCR, se les determinaron 10 polimorfismos en la vía del folato. Durante 5 años de seguimiento se determinó la sobrevida libre de enfermedad y la sobrevida total, y su relación con su genotipo. Resultados: Cuatro polimorfismos no estuvieron en equilibrio de Hardy-Weinberg COL18A1(rs2274808), ABCC5(rs9838667 y rs3792585) y XO(rs17011368). Únicamente el rs17011368 de XO se asoció con riesgo de estar presente en los pacientes con leucemia linfoblástica aguda cuyo OR fue 9.771 p=0,001). El FPGS (rs1544105) afectó la sobrevida libre de enfermedad y la sobrevida total (Log Rank p<0.05). Conclusiones: El polimorfismo (rs17011368) de la XO presentó riesgo para leucemia linfoblástica aguda; así mismo, se encontró una asociación importante entre los portadores del polimorfismo FPGS (rs1544105) que modificaría la sobrevidas de los pacientes tratados con MTX.Palabras clave: Metotrexato, xantina oxidasa, supervivencia, leucemia linfoblástica, genotipo. ABSTRACTBackground: Acute lymphoblastic leukemia (ALL) is a major cancer disease in Mexican pediatric population, were the genotype could affect the effectiveness of chemotherapy in which the methotrexate (MTX) is involved and consequently the time of disease free survival and overall survival. Objective: Determine the association of 10 genetic polymorphisms of the folate pathway: in cellular carriers SLC19A1, ABCB1 and ABCC5) and in enzymes such as folylpolyglutamate synthetase (FPGS) and xanthine oxidase (XO), with survival of children with acute lymphoblastic leukemia. Methods: Thirtynine children with acute lymphoblastic leukemia from the State Cancer Center in Durango (Mexico) treated with MTX and 102 healthy controls, were qPCR analyzed for 10 polymorphisms in the folate pathway. During 5 years of follow up, the disease-free survival and overall survival rates were investigated in relation with their genotypes. Results: Four polymorphisms were not found in Hardy-Weinberg Equilibrium COL18A1 (rs2274808), ABCC5 (rs9838667 and rs3792585) and XO (rs170113685). Only XO (rs170113685) was associated with risk of being present in patients with ALL whose odds ratio was 9.771 (95% 4.974-19.196, p=0.001). The polymorphism rs1544105 for FPGS affected disease free survival and overall survival (Log Rank tes...

Doxorubicin (DOX) is a highly useful antineoplastic in the treatment of different types of cancer; however, its use is limited due to its wide variability between patients in their susceptibility to the cardiotoxic effects of anthracyclines. Purpose: The aim of this study was to determine the effect of single nucleotide variants (SNV) and the nutritional status on the population pharmacokinetics of DOX, and their repercussions on cardiotoxicity in pediatric patients with leukemia. Patients and methods: Seventy pediatric patients treated with DOX were studied, in whom 189 biological samples (1 to 3 samples per patient) were obtained at different random times, for 20 hours. Results: Body mass index, age ≤ 7 years and female sex were associated with a decrease in DOX clearance. Low height was associated with an increase in pharmacokinetics parameters of DOX. The Wild type (WT) genotype of ABCC1 rs3743527 variant was associated with an increase in clearance (CL), and the homozygous variant (HV) genotype of NCF4 rs1883112 SNV was associated with a decrease in peripheral compartment (V2) of the peripheral compartment. Conclusion: The SNV of the ABCC1 and NCF4 genes influence the increase and decrease in DOX CL, in addition, characteristics such as sex and height were associated with the decrease and increase in DOX CL respectively. The pharmacokinetic parameters show an influence on the development of cardiotoxicity by DOX. The decrease in CL and V2 were associated with systolic disfunction. The decrease in the intercompartmental clearance (Q) and in the volume distribution (V2) were associated with diastolic disfunction. In clinical practice, these results may contribute to the effective and safe use of DOX in pediatric cancer patients.

Doxorubicin (DOX) is a highly useful antineoplastic in the treatment of different types of cancer; however, its use is limited due to its wide variability between patients in their susceptibility to the cardiotoxic effects of anthracyclines. Purpose: The aim of this study was to determine the effect of single nucleotide variants (SNV) and the nutritional status on the population pharmacokinetics of DOX, and their repercussions on cardiotoxicity in pediatric patients with leukemia. Patients and methods: Seventy pediatric patients treated with DOX were studied, in whom 189 biological samples (1 to 3 samples per patient) were obtained at different random times, for 20 hours. Results: Body mass index, age ≤ 7 years and female sex were associated with a decrease in DOX clearance. Low height was associated with an increase in pharmacokinetics parameters of DOX. The Wild type (WT) genotype of ABCC1 rs3743527 variant was associated with an increase in clearance (CL), and the homozygous variant (HV) genotype of NCF4 rs1883112 SNV was associated with a decrease in peripheral compartment (V2) of the peripheral compartment. Conclusion: The SNV of the ABCC1 and NCF4 genes influence the increase and decrease in DOX CL, in addition, characteristics such as sex and height were associated with the decrease and increase in DOX CL respectively. The pharmacokinetic parameters show an influence on the development of cardiotoxicity by DOX. The decrease in CL and V2 were associated with systolic disfunction. The decrease in the intercompartmental clearance (Q) and in the volume distribution (V2) were associated with diastolic disfunction. In clinical practice, these results may contribute to the effective and safe use of DOX in pediatric cancer patients.