RESUMEN
Although surgical resection is the standard curative therapy for gastric cancer, these tumors are often diagnosed at an advanced stage, when surgery is not recommended. Alternative treatments such as radiotherapy and chemotherapy achieve only very modest results. There is therefore an urgent need to advance in this field of oncologic gastroenterology. The poor response of gastric cancer to chemotherapy is usually due to a combination of mechanisms of chemoresistance (MOC), which may include a reduction in drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), a reduced proportion of active agents in tumor cells due to a reduction in pro-drug activation or an enhancement in drug inactivation (MOC-2), changes in the expression/function of the molecular targets of anticancer drugs (MOC-3), an enhanced ability of cancer cells to repair anticancer drug-induced DNA damage (MOC-4), and decreased expression/function of pro-apoptotic factors or up-regulation of anti-apoptotic genes (MOC-5). Two major goals of modern pharmacology aimed at overcoming this situation are the prediction of a lack of response to chemotherapy and the identification of the underlying mechanisms accounting for primary or acquired refractoriness to anticancer drugs. These are important issues if we are to select the best pharmacological regime for each patient and develop novel strategies to overcome chemoresistance. The present review reports updated information regarding the mechanisms of chemoresistance (from MOC-1 to MOC-5) in gastric cancer, the advances made in the prediction of the failure of chemotherapeutic treatment, and novel strategies based on gene therapy currently being developed to treat these tumors.
Asunto(s)
Antineoplásicos/farmacología , Citocromo P-450 CYP2A6/metabolismo , Resistencia a Antineoplásicos , Transportadores de Anión Orgánico ATP-Dependiente/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carboxilesterasa/genética , Carboxilesterasa/metabolismo , Citocromo P-450 CYP2A6/genética , Reparación del ADN/efectos de los fármacos , Terapia Genética , Humanos , MicroARNs/uso terapéutico , Terapia Molecular Dirigida , Estadificación de Neoplasias , Transportadores de Anión Orgánico ATP-Dependiente/genética , Proteínas de Transporte de Catión Orgánico/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
The barrier epithelia of the cornea and retina control drug and nutrient access to various compartments of the human eye. While ocular transporters are likely to play a critical role in homeostasis and drug delivery, little is known about their expression, localization and function. In this study, the mRNA expression levels of 445 transporters, metabolic enzymes, transcription factors and nuclear receptors were profiled in five regions of the human eye: cornea, iris, ciliary body, choroid and retina. Through RNA expression profiling and immunohistochemistry, several transporters were identified as putative targets for drug transport in ocular tissues. Our analysis identified SLC22A7 (OAT2), a carrier for the antiviral drug acyclovir, in the corneal epithelium, in addition to ABCG2 (BCRP), an important xenobiotic efflux pump, in retinal nerve fibers and the retinal pigment epithelium. Collectively, our results provide an understanding of the transporters that serve to maintain ocular homeostasis and which may be potential targets for drug delivery to deep compartments of the eye.
Asunto(s)
Ojo/metabolismo , Perfilación de la Expresión Génica/métodos , Transportadores de Anión Orgánico ATP-Dependiente/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Aciclovir/metabolismo , Córnea/metabolismo , Humanos , Inmunohistoquímica , Técnicas In Vitro , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transportadores de Anión Orgánico ATP-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Retina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Vitamin C is a wide spectrum antioxidant essential for humans, which are unableto synthesize the vitamin and must obtain it from dietary sources. There are two biologicallyimportant forms of vitamin C, the reduced form, ascorbic acid, and the oxidizedform, dehydroascorbic acid. Vitamin C exerts most of its biological functionsintracellularly and is acquired by cells with the participation of specific membranetransporters. This is a central issue because even in those species capable of synthesizingvitamin C, synthesis is restricted to the liver (and pancreas) from which is distributedto the organism. Most cells express two different transporter systems for vitaminC; a transporter system with absolute specificity for ascorbic acid and a secondsystem that shows absolute specificity for dehydroascorbic acid. The dehydroascorbicacid transporters are members of the GLUT family of facilitative glucose transporters,of which at least three isoforms, GLUT1, GLUT3 and GLUT4, are dehydroascorbicacid transporters. Ascorbic acid is transported by the SVCT family ofsodium-coupled transporters, with two isoforms molecularly cloned, the transportersSVCT1 y SVCT2, that show different functional properties and differentialcell and tissue expression. In humans, the maintenance of a low daily requirement ofvitamin C is attained through an efficient system for the recycling of the vitamininvolving the two families of vitamin C transporters (AU)
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Asunto(s)
Humanos , Masculino , Femenino , Ácido Ascórbico/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 3/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Transportadores de Anión Orgánico ATP-Dependiente/metabolismo , Transportadores de Anión Orgánico ATP-Dependiente/farmacología , Simportadores/metabolismo , Simportadores/farmacología , Simportadores/fisiología , Ácido Ascórbico/uso terapéutico , Ácido Deshidroascórbico/metabolismo , Ácido Deshidroascórbico/farmacologíaRESUMEN
The action of extracellular ATP on organic anion transport in the bivascularly perfused rat liver was investigated, using bromosulfophthalein as a model substance. Transport was measured by means of the multiple-indicator dilution technique. The action of portal 100 microM ATP presented the following characteristics: (a) inhibition of bromosulfophthalein single pass extraction; the inhibition degree decreased with increasing bromosulfophthalein doses; (b) diminution of the influx rate coefficients; (c) 86.7% decrease of the maximal activity of the saturable component for bromosulfophthalein transport, but 100% increase of the non-saturable component; (d) diminution of the bromosulfophthalein flow-limited distribution space; (e) no significant alteration of the rate coefficients for metabolic sequestration. The action of ATP on organic anion transport in the intact liver occurred at much lower concentrations (10x) than those previously reported for isolated hepatocytes. This reinforces the suggestion that inhibition of organic anion transport could be a physiologically relevant effect of extracellular ATP.
Asunto(s)
Adenosina Trifosfato/farmacología , Espacio Extracelular/efectos de los fármacos , Hígado/efectos de los fármacos , Sulfobromoftaleína/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Relación Dosis-Respuesta a Droga , Espacio Extracelular/metabolismo , Hígado/metabolismo , Masculino , Transportadores de Anión Orgánico ATP-Dependiente/antagonistas & inhibidores , Transportadores de Anión Orgánico ATP-Dependiente/metabolismo , Perfusión/métodos , Ratas , Ratas WistarRESUMEN
The intracellular fluorescence level of cells stained continuously with monochlorobimane was monitored by flow cytometry in order to assess the initial rate of glutatione to monochlorobimane conjugation as a measure of glutathione S-transferase activity. In addition to a rapid initial increase and a plateau level, a decline in fluorescence intensity was found upon prolonged flow cytometric monitoring. Exposure to probenicid, an inhibitor of an ATP-dependent organic anion pump, prevented this decrease. Incubation with vanadate and verapamil was without effect. Thus, extrusion of fluorescentglutathione-conjugate perturbs the proportionality between initial glutathione level and monochlorobimane-dependent fluorescence intensity. Monitoring by flow cytometry the decrease in monochlorobimane-dependent fluorescence may be useful to detect multidrug resistant cells.