Farmacogenómica del tratamiento de primera línea en el cáncer gástrico: avances en la identificación de los biomarcadores genómicos de respuesta clínica / Pharmacogenomics of the first-line treatment for gastric cancer: advances in the identification of genomic biomarkers for clinical response to chemotherapy

Debido a la inespecificidad de los síntomas, el cáncer gástrico (CG) es diagnosticado frecuentemente en etapas avanzadas, lo que da cuenta de los altos índices de mortalidad debido a esta neoplasia a nivel mundial. El esquema de tratamiento adyuvante o neoadyuvante en los países occidentales incluye el uso de fluoropirimidinas citotóxicas y compuestos de platino formadores de aductos en el ADN. La respuesta clínica al tratamiento con estos fármacos depende principalmente de la sensibilidad del tumor, la cual a su vez está condicionada por el nivel de expresión de los blancos terapéuticos y de las enzimas de reparación del ADN. Sumado a esto, algunos polimorfismos de línea germinal en genes asociados al metabolismo y a la respuesta a estos fármacos, han mostrado asociación con respuestas pobres y con el desarrollo de eventos adversos, incluso con resultados fatales. La identificación de biomarcadores genómicos, en la forma de polimorfismos genéticos o la expresión diferencial de genes específicos asociados a la respuesta quimioterapeútica ha sido motivo de intensa investigación como base para la aplicación de la farmacogenómica en el establecimiento de una terapia farmacológica racional y personalizada del CG. Sin embargo, ante la eventual aplicación de la farmacogenómica en el ámbito clínico, es necesario establecer el valor pronóstico real de dichos biomarcadores mediante los estudios de asociación genotipo-fenotipo, así como su prevalencia en el contexto de cada población de pacientes. Estos aspectos son indispensables al evaluar la relación costo-efectividad de la introducción de los productos de la medicina genómica predictiva en el tratamiento del CG.

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.

Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study / Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto

Introduction.Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). Objective.This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. Materials and methods. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Results. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Conclusions. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteers.

Introducción. El levonorgestrel, un progestágeno sintético usado para endometriosis, dismenorrea y anticoncepción de emergencia, es rápida y completamente absorbido en el tubo digestivo. Su metabolismo es principalmente hepático, mediante las enzimas CYP3A4 y CYP3A5. Objetivo. El presente estudio tuvo como objetivo evaluar la asociación entre la farmacocinética de levonorgestrel y las variantes alélicas de CYP3A4*1B y CYP3A5*3. Materiales y métodos. En un grupo de 17 mujeres adultas sanas, que firmaron un consentimiento informado, se practicó genotipificación para CYP3A4*1B y CYP3A5*3 mediante PCR. Posteriormente, las voluntarias fueron sometidas a un estudio farmacocinético donde, luego de 12 horas de ayuno, recibieron una dosis de 0,75 mg de levonorgestrel. Se extrajeron muestras sanguíneas seriadas (0 a 24 horas) y se determinaron las concentraciones de levonorgestrel mediante un método validado de UPLC-ms/ms, para luego obtener los parámetros farmacocinéticos. Todos los procedimientos consideraron los aspectos éticos de la Declaración de Helsinki y las buenas prácticas clínicas. Resultados. Las frecuencias genotípicas observadas para el grupo de estudio fueron 11,8 % para *1B/*1B; 5,8 % para *1/*1B, y 82,4 % para *1/*1 de CYP3A4*1B. Para CYP3A5*3, las frecuencias genotípicas fueron 70,5 % para *3/*3; 23,5 % para *1/*3, y 6,5 % para *1/*1. Se observa una interesante variabilidad entre las voluntarias que sugiere una relación con las variantes genéticas CYP3A, pero que no permite establecer una asociación estadísticamente significativa, presumiblemente debido al bajo número de individuos homocigotos mutados de CYP3A4 y silvestres de CYP3A5. Conclusiones. Los polimorfismos genéticos podrían ser factores relevantes en la determinación de la variabilidad entre pacientes en las concentraciones plasmáticas de levonorgestrel, lo cual, sin embargo, no pudo ser establecido estadísticamente en este estudio. Por lo tanto, resulta necesario continuar este tipo de estudios con mayor número de voluntarios para establecer una asociación entre la variabilidad observada y la presencia de estos polimorfismos.

Biotransformación de carbón de bajo rango por bacterias aisladas de microhábitats influenciados por residuos de carbón / Biotransformation of low rank coal by bacteria isolated from environments influenced by coal residue

Se describió la capacidad de cinco cepas bacterianas para transformar un carbón de bajo rango (CBR), para ello se evaluaron cepas aisladas de microhábitats con presencia de partículas procedentes de los procesos de almacenamiento y lavado de carbón en la mina El Cerrejón (Colombia). Se realizaron ensayos de solubilización de CBR en medio de cultivo sólido y líquido, además de la decoloración de sustancias húmicas (SH) extraídas del CBR. Todas las bacterias evaluadas presentaron capacidad para biotransformar CBR en medio sólido, esta actividad es mayor cuando el CBR ha sido pretratado con ácido nítrico; en medio líquido se alcanzó una pérdida de peso de CBR hasta del 37% por acción de una cepa de Acinetobacter baumannii, acompañada de la aparición de hasta 8,06 mg/ml-1 de sustancias solubles con absorbancia a 465 nm; los cambios en el pH del medio sugieren que la actividad biotransformadora de CBR está asociada a la liberación de sustancias alcalinas; finalmente, se encontró evidencia para sugerir que las SH presentes en el CBR son transformadas por cometabolismo, posiblemente mediante reacciones de depolimerización, decoloración y repolimerización.

in this study were evaluated five bacterial strains isolated from microhabitats with high content of coal particles generated from storage and washing processes, in "The Cerrejón” open coal mine (Colombia), their ability to biotransform a low rank coal (LRC) was described by testing solubilization on solid and liquid culture medium, as well as bleaching of humic substances (HS) extracted from LRC. All tested bacteria showed ability to biotransform LRC on solid medium, this activity is greater when the LRC has been pretreated with nitric acid; in liquid medium LRC reached 37% of weight loss by Acinetobacter baumannii strain, accompanied by the appearance of up to 6.8 mg/ml-1 of soluble substances with absorbance at 465 nm, changes in culture medium pH suggest that LRC biotransformations activity is associated with alkaline substances release, finally found evidence to suggest that HS contained within LRC are transformed by cometabolism, possibly by depolymerization reactions, bleaching and repolimerization.

Famacogénica del cáncer: Estudio de variaciones genéticamente determinadas en la susceptibilidad a cáncer por exposición a xenobióticos / Cancer pharmacogenetics: Study of genetically determined variations on cancer susceptibility due to xenobiotic exposure

Pharmacogenetics is the study of genetically determined variations in the response to drugs and toxic agents, and their implications on disease. Recently, the discipline has acquired great relevancy due to the development of non-invasive molecular techniques that identify genetic variants in human beings. There is also a need to explain the individual differences in susceptibility to drug actions and disease risk. Genetic variants can modify the magnitude of a pharmacologic effect, toxicity threshold, secondary effects and drug interactions. There are approximately thirty families of drug-metabolizing enzymes with genetic variants that cause functional alterations and variations in pharmacologic activity. We summarize the general knowledge about genetic variants of biotransformation enzymes, their relationship with cancer risk and the role of ethnicity. Cancer pharmacogenetics is another promising and exciting research area that will explain why people with an almost identical group of genes, have a different susceptibility to cancer, whose etiology has genetic and environmental components.

Acetylator phenotype in Iraqi patients with systemic lupus erythematosus

The study was designed to determine the acetylator status in patients with systemic lupus erythematosus [SLE] and compare it to a matched group of healthy volunteers. Disease severity was determined using the revised American College of Rheumatology criteria for classification and the SLE disease activity index. After an overnight fast, each participant received a single oral dose of 100 mg dapsone. After 3 hours, plasma dapsone/monoacetyldapsone ratio was determined. In the control group, frequency of slow acetylators was 73.3%; frequency of rapid acetylators was 26.7%. In SLE patients, frequency of slow acetylators was 78.0%; frequency of rapid acetylators was 12.0%. However, 8.0% were non-acetylators [monoacetyldapsone not detected in plasma]. There was no association between acetylator status and severity of SLE

Acetylator status, drug metabolism and disease.

Acetylation polymorphism, although discovered 40 years ago, still holds interest not only because many drugs and carcinogens are metabolized by acetylation in the liver but also because advances have been made in the understanding of the molecular genetics of acetylation. It is this genetic variation of drug metabolism that is one of the causes of inter-individual variation of the effect of a drug. Acetylation polymorphism relates to the metabolism of a number of arylamine and hydrazine drugs and carcinogens by cytosolic N-acetyltransferase--NAT2. In humans, 2 genes--NAT1 and NAT2--are responsible for the N-acetyltransferase activity. Studies have revealed several allelic variants of both NAT1 and NAT2. It has been suggested that some of these variants modify the individual susceptibility to disease.