Impact of single-nucleotide variants and nutritional status on population pharmacokinetics of Doxorubicin, and its effect on cardiotoxicity in children with leukemia.

PURPOSE:  Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects. To determine the effect of genotypic status of three single-nucleotide variants in ABCC1, NCF4, and CBR3 genes and nutritional status assessed by body mass index, on the population pharmacokinetics of Doxorubicin and its cardiotoxic effects in pediatric patients with leukemia. PATIENTS AND METHODS: Seventy pediatric patients treated with Doxorubicin were studied, in which 189 biological samples were obtained to determine Doxorubicin concentrations (1 to 3 samples per patient) at different times, for 20 h. RESULTS: Low body mass index and age ≤ 7 years were associated with decreased clearance of Doxorubicin, and female gender was associated with increased clearance of Doxorubicin. Low BMI and low height were associated with a decrease and increase, respectively, in the intercompartmental clearance (Q) of Doxorubicin. TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene was associated with an increase in clearance and decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene was associated with a decrease in the volume of distribution in the peripheral compartment (V2), and GG homozygosity of CBR3 rs1056892 with increasing area under the curve. CONCLUSION: Some covariates studied are directly related to the increase or decrease of the pharmacokinetic parameters of Doxorubicin. Decreased clearance, V2, and increased area under the curve were associated with systolic dysfunction, and decreased Q and V2 were associated with diastolic dysfunction. These results may contribute to the effective and safe use of Doxorubicin in pediatric patients with leukemia.

Association of genetic polymorphisms NCF4 rs1883112, CBR3 rs1056892, and ABCC1 rs3743527 with the cardiotoxic effects of doxorubicin in children with acute lymphoblastic leukemia.

OBJECTIVES: Cardiotoxicity is a frequent complication secondary to the use of anthracyclines for cancer chemotherapy. Evidence suggests that certain polymorphic genetic variants modify the risk for anthracycline-related cardiotoxicity. Reports documenting the impact of genetic polymorphisms on anthracycline-cardiotoxicity risk in pediatric patients with cancers from Latin American countries are scarce. The objective of this study was to evaluate associations between NCF4 rs1883112, CBR3 rs1056892 and ABCC1 rs3743527 genotype status and echocardiographic parameters indicative of anthracycline-cardiotoxicity in a group of Mexican children with acute lymphoblastic leukemia (ALL). METHODS: Sixty-seven children (2-18 years old) with ALL were treated at the State Cancer Center in Durango, Mexico. NCF4, CBR3, and ABCC1 genotypes were examined by real-time PCR. Left ventricular ejection fraction and diastolic filling ratio were examined as markers of systolic and diastolic anthracycline-toxicity. RESULTS: NCF4 rs1883112 genotype status was significantly associated with the risk of doxorubicin cardiotoxicity [odds ratio (OR) = 10.80, 95% confidence interval (CI) 1.69-68.98, P = 0.01]. There was a significant association between heterozygous CBR3 rs1056892 genotype status and anthracycline-cardiotoxicity risk (OR = 9.91, 95% CI 1.07-91.47, P = 0.04). Heterozygosis for the ABCC1 rs3743527 allele was associated with protection from anthracycline-cardiotoxicity (OR = 0.30, 95% CI 0.09-0.91, P = 0.03). CONCLUSION: This pilot study suggests that selected polymorphic variants may impact the risk for anthracycline-cardiotoxicity in pediatric patients with ALL treated with a contemporary chemotherapeutic regimen in Mexico.

Leptin levels and nutritional status of indigenous Tepehuán and Mestizo subjects in Durango, Mexico.

The aim of this study was to assess differences in nutritional status and their association with circulating leptin levels in the indigenous Tepehuán people of Mezquital Durango and Mestizo populations of Durango City, Mexico. A group of 128 volunteers aged 18 through 59 years were recruited for the study: 60 indigenous Tepehuán from Mezquital and 68 Mestizo individuals from Durango City. The classification of nutritional status was through body mass index (BMI). Clinical evaluations, including anthropometry and lipid profiles, were performed to ascertain the health of the participants. Circulating leptin levels were determined in blood samples after at 08 hours of fasting. The healthy subjects were classified according to BMI: 32 Tepehuán and 30 Mestizo subjects were of normal weight (NW), and 28 Tepehuán and 38 Mestizo subjects were overweight or obese (OW/O). Both NW and OW/O Tepehuán subjects showed lower leptin concentrations than the comparable Mestizo subjects. Statistical analysis showed a negative Pearson's correlation (r = -0.5; P < 0.05) between BMI and leptin levels in NW Tepehuán subjects, but no significant correlation was found in other groups. The differences found in Tepehuán compared with Mestizo subjects might be explained by poor nutritional status, which leads to scarce adipose tissue and low levels of leptin synthesis. Leptin concentration and its relationship to BMI are associated with ethnicity.

Morbilidad y mortalidad por cáncer: experiencia del Centro Estatal de Cancerología de la SSA del Estado de Durango, México / Morbidity and mortality from cancer: experience of the State Center of Cancer from the SSA of Durango State, Mexico

OBJETIVO: En este estudio evaluamos el primer reporte de las estadísticas del cáncer en el Centro Estatal de Cancerología (CEC-Durango), México. MÉTODOS: Se realizó un estudio longitudinal retrospectivo, del período comprendido de enero de 2001 a diciembre de 2003, para conocer la morbimortalidad por cáncer de acuerdo con el sexo y edad, identificando sus características y tendencias. RESULTADOS: Desde la niñez hasta los 64 años de edad se observó un incremento en el número de casos, para disminuir en las últimas etapas de la vida. Durante la etapa pediátrica existe una alta tasa de casos de leucemia para niños y niñas, seguidas de tumores del sistema nervioso central (SNC) en niños y de osteosarcomas en las niñas. En los adultos, la mayoría de casos se observaron entre los 55 y 64 años de edad, para disminuir en la senescencia. Existen más casos en mujeres que en hombres; el cáncer cervicouterino (CaCu) y el cáncer de mama ocupan el primer lugar en las mujeres, y los tumores del SNC y el cáncer de pulmón en los hombres. El número total de casos disminuye conforme aumenta la edad de los sujetos. CONCLUSIONES: Hay diferencias en la morbilidad y la mortalidad por cáncer de acuerdo con la etapa de crecimiento y desarrollo de los individuos. La tasa de mortalidad general fue de 10 por ciento del total de casos. La mortalidad se vio incrementada exponencialmente a medida que se incrementa la edad de los sujetos. La mayoría de las muertes correspondió a grupos entre 15 a 24 años de edad y de 45 a 64 años en los hombres, y en las mujeres de 35 a 44 años, y después de los 65 años en ambos grupos.

PURPOSE: In this study, we evaluate the first report of cancer statistics of the Oncology State Center-Durango Mexico. METHODS: This is a retrospective longitudinal analysis of morbidity and mortality from cancer according to chronological age. RESULTS: From childhood to 64 years it was observed an increase in the number of cases to decrease in latter stages. On pediatrics age, there is a high rate of cases of leukemia for boys and girls, followed by Central Nervous System (CNS) tumors in boys and osteosarcomas in girls. For adults, most of cases were observed between 55 and 64 years to decrease in senescent. There are more cases in women than in men; cervical intraepithelial neoplasia (CIN) and breast cancer, for the former and CNS tumors and lung cancer for the last. The whole number of cases decreases as age increases. CONCLUSIONS: There are differences in morbidity and mortality from cancer according to stage of growth and development of the individuals. The general mortality rate was 10 percent of total cases. The mortality was increased exponentially as age increases. The majority of deaths corresponded to groups between 15 to 24 years and 45 to 64 years in men, 35 to 44 years and after 65 years in women.