Mechanisms of Resistance to Chemotherapy in Gastric Cancer.

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.

Gene expression profiling of transporters in the solute carrier and ATP-binding cassette superfamilies in human eye substructures.

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.

Vitamin C transporters

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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Transporters in the intestine limiting drug and toxin absorption

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The pharmacokinetic behaviour of drugs strongly depends on transporters inintestine and liver. The extent of absorption in the intestine depends on diffusionacross the mucosa as well as transporter-mediated uptake across the apical membraneof enterocytes. Efflux pumps in this membrane may strongly reduce the extent of netuptake. These efflux pumps are ATP-binding cassette (ABC) transporters which arealso expressed in the apical membrane of the hepatocyte were they mediate excretioninto bile. This combined activity strongly determines whether drugs have access tothe systemic circulation (AU)

Comparison of urinary excretion of phenolsulfonphthalein in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Wistar rats: involvement of primary active organic anion transporter.

PURPOSE: The aim of this study was to determine the cause of the decline in phenolsulfonphthalein (PSP) excretion in Long-Evans Cinnamon (LEC) rats. METHODS: The uptake of PSP into rat renal basolateral membrane vesicles (BLMV) was studied. Cyclosporin A (CYA) was used to modulate an ATP-dependent primary active transporter. PSP was intravenously injected into rats with or without CYA. The transcellular transport of PSP was examined by using primary cultured renal proximal tubule cells (PTC). RESULTS: No significant difference was found between the uptake of PSP into renal BLMV of Wistar rats and that into renal BLMV of LEC rats. In the presence of CYA, the urinary excretion and the plasma concentrations of PSP in Wistar rats were decreased and increased, respectively. In primary cultured renal PTC from Wistar rats, the basal-to-apical transport of PSP was greater than that in the opposite direction and the basal-to-apical transport of PSP was substantially reduced by the addition of CYA. However, CYA did not affect the basal-to-apical transport of PSP in PTC from LEC rats. CONCLUSIONS: The results suggest that PSP is transported by primary active organic anion transporter and that the activity level of this transporter is reduced in LEC rats.

Inhibition by extracellular ATP of organic anion transport in the perfused rat liver.

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.

Probenicid inhibition of fluorescence extrusion after MCB-staining of rat-1 fibroblasts.

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.