Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.
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PMID:Intrinsic drug resistance in primary and metastatic renal cell carcinoma. 1037 90

Multidrug resistance-associated protein gene MRP/MRP1, and its family genes, including MRP2/cMOAT, have been isolated and characterized. These ATP-binding cassette (ABC) superfamily transporter genes are differentially expressed in various normal tissues and multidrug-resistant cell lines. Transfection of MRP/MRP1 and MRP2/cMOAT cDNA confers drug resistance on different spectra of anticancer agents from that of MDR1 coding P-glycoprotein. Although it remains unclear how MRP/MRP1 and related family genes are specifically involved in drug resistance in clinical cancers, current knowledge of the MRP subfamily suggests the importance of this class of transporters as a molecular target for drug sensitivity to anticancer agents.
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PMID:Multidrug resistance-associated protein subfamily transporters and drug resistance. 1040 39

In order to bring MDR analysis into a clinical setting, reproducible assays with clear cut off points to define MDR positivity must be used. Sensitivity can also be increased by combining the results of more than one assay. We have used a combination of flow cytometric assays to define MDR positive and negative blasts in 47 AML patients entered into MRC trials. Our primary test is a standardised and reproducible assay for anthracycline accumulation in which we use carboxylate microspheres to bind the fluorescent drug daunorubicin (dnr). Cells and beads are incubated concurrently with dnr. Cellular dnr accumulation is quantified as a cell:bead fluorescence ratio. Confirmatory assays for MDR comprise the cyclosporin modulation assay for rhodamine 123 uptake and also measurement of lung resistance protein and multidrug resistance associated protein (with LRP-56 and MRPr1 respectively). 27/47 (57%) samples had both low and accumulation and at least one positive confirmatory test (a modulated functional assay and/or protein overexpression) and were categorised as "confirmed MDR". 15/47 patients (32%) were MDR negative in all 4 assays. 5/47 (11%) patients had unconfirmed low dnr accumulation. None of the patients in this cohort had high dnr accumulation alongside overexpressed LRP or MRP or functional P-glycoprotein. We believe that this approach to MDR analysis enhances the value of the highly reproducible functional assays. The use of a primary and confirmatory tests is also likely to improve specificity.
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PMID:Reproducible flow cytometric methodology for measuring multidrug resistance in leukaemic blasts. 1050 Jul 83

In this manuscript, our recent studies on the transporters on the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier responsible for the excretion of ligands from the central nervous system (CNS) to the blood are summarized. By comparing the brain entry of quinidine in normal and mdr 1a knock out mice, the predominant role of P-glycoprotein in the brain distribution of this compound was demonstrated. In addition to P-glycoprotein, the presence of transporters responsible for the efflux of organic anions from the brain has been suggested by a pharmacokinetic analysis of the CNS distribution of cefodizime, a third generation cephalosporin antibiotic. This suggestion was confirmed by demonstrating the presence of a specific mechanism for the elimination of p-aminohippuric acid from the brain after microinjection into the cerebral hemisphere. In vitro, the energy-dependent luminal preferential efflux of glutathione-bimane was demonstrated in a monolayer of MBEC4 cells which were derived from mouse brain endothelial cells. Studies with isolated membrane vesicles from MBEC4 cells suggested the presence of a primary active transporter(s) for organic anions, and Western blot analysis indicated the presence of multidrug resistance associated protein (MRP1) and/or its related transporters on MBEC4 cells and freshly isolated rat cerebral endothelial cells. The transcellular transport of 17beta estradiol 17beta-D-glucuronide (E(2)17betaG) across the choroid plexus was also demonstrated by examining the efflux of this compound from CSF after intracerebroventricular administration. The functional significance of organic anion transporting polypeptide (oatp-1) on the brush border membrane of the choroid plexus was demonstrated by comparing the uptake of E(2)17betaG into the isolated choroid plexus and oatp-1 transfected COS-7 cells; in addition, reverse transcription-polymerase chain reaction and Western blot analysis indicated the presence of MRP in the choroid plexus. Together with the direction of transcellular transport, the basolateral localization of MRP on the choroid plexus was suggested. By regulating the activity of these efflux transporters, it is possible to improve the brain entry of certain substrates.
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PMID:Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain. 1051 49

The Caco-2 cell monolayer has become an increasingly useful in-vitro model of human intestinal absorption. In this study we have determined the effect of plasma on the basolateral side on the absorption as well as exsorption of several drugs that are highly bound to plasma proteins. The drugs used included propranolol and quercetin, which both use the transcellular route of absorption, and taxol and oestradiol 17 beta-D-glucuronide, which are thought to undergo efflux by P-glycoprotein and the multidrug resistance protein MRP, respectively. All experiments were carried out under sink conditions to mimic normal absorption. It was necessary to use heparin anticoagulation for generation of the plasma, as EDTA was found to make the monolayers very leaky. The apparent permeability (P(app)) values for absorption were 1.54 x 10(-6) cm s(-1) for oestradiol 17 beta-D-glucuronide, 3.33 x 10(-6) cm s(-1) for taxol, 20.8 x 10(-6) cm s (-1) for quercetin, and 35.3 x 10(-6) cm s(-1) for propranolol. For these four compounds, plasma on the basolateral side had no influence on absorption. However, plasma on the basolateral side significantly reduced the efflux of oestradiol 17 beta-D-glucuronide by 66%, taxol by 75%, propranolol by 82%, and quercetin by 94%. Failure to consider the effect of plasma binding can result in an overestimate of basolateral to apical efflux and result in misleading net flux calculations.
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PMID:The influence of plasma binding on absorption/exsorption in the Caco-2 model of human intestinal absorption. 1052 87

Breast cancer is a chemosensitive tumour and anthracyclines are one of the most active cytotoxic agents in chemotherapy treatment. Failure after anthracycline-containing chemotherapy is a poor prognostic factor because of low response rate to salvage chemotherapy. Several factors like P-glycoprotein mediated drug resistance (MDR-1 or MRP), glutathione or amplification of topoisomerase II have been found to be involved in anthracycline resistance. No clear benefit for patients treated with 'resistance-modifier' agents like verapamil, dexverapamil or quinidine has yet been demonstrated. Most clinical studies with non-cross resistant cytotoxic agents are lacking a strict definition of anthracycline resistance. A strict definition of anthracycline resistance implies progressive disease during anthracycline chemotherapy. Among the cytotoxic drugs only 5-Fluorouracil (given as 24 h continuous infusion with folinic acid) and the taxanes produce more than 20% objective remission (RR) in case of anthracycline resistance, whereas the highest response rate was reported for docetaxel (32-57%). Only few randomized studies were performed: docetaxel showed higher anti-tumor activity than methotrexat/5-FU (RR: 42% vs 19%, P<0.001) or mitomycin/vinblastine (RR: 30% vs 12%;P<0.001) and treatment with paclitaxel (175 mg/m(2)) was in favour to mitomycin (RR 17% vs 6%). In combination chemotherapy most activity have been reported for paclitaxel plus high-dose 5-fluorouracil (given as 24 h continuous infusion with folinic acid) (RR: 58%) or for docetaxel plus cisplatinum (RR: 46%). High-dose regimens with growth factor or stem cell support seems to be active in anthracycline-resistant disease but the toxicity is considerable. In conclusion, the taxanes, especially docetaxel as single agent or paclitaxel plus high-dose 5-FU, are the most promising therapeutic options in treatment of anthracycline resistant disease. Further clinical phase II/III studies in breast cancer should include exact definition of anthracycline pretreatment and resistance.
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PMID:Current options in treatment of anthracycline-resistant breast cancer. 1054 72

Resistance to cytotoxic drugs is an important cause of treatment failure. The causes are complex and may be determined by a combination of the tumour characteristics, such as the proportion of resting cells, adequacy of blood supply, and specific cellular mechanisms, as in the multidrug resistance phenotype. In lung cancer four types of multidrug resistance have been defined on the basis of the cellular drug targets involved, i.e., classical multidrug resistance (MDR), non-P-glycoprotein MDR (also called MRP), atypical MDR (mediated through altered expression of topoisomerases II) and lung resistance-related protein. In lung cancer the role of the different forms of multidrug resistance is complex and only partially understood.
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PMID:Multidrug resistance in non-small-cell lung cancer. 1058 46

The excretion of drugs mediated by transporters plays an important role in the detoxification of xenobiotics. In this article, I will summarize recent progress we have made in this field, particularly focusing on the roles of transporters responsible for exporting drugs. As far as the biliary excretion of xenobiotics is concerned, it has been suggested that canalicular multispecific organic anion transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) is involved in the ATP-dependent export of organic anions across the bile canalicular membrane. By comparing the transport across this membrane between normal rats and Eisai hyperbilirubinemic rats whose cMOAT/MRP2 function is hereditarily defective, we were able to demonstrate the substrate specificity of cMOAT/MRP2. This includes non-conjugated anionic drugs, and glutathione- and glucuronide-conjugates of xenobiotics. The role of cMOAT/MRP2 in drug disposition has also been clarified. Moreover, the cDNA of cMOAT/MRP2 has been cloned and its functional analysis has been completed. Thus, it may be possible to predict in vivo transport across the bile canalicular membrane from in vitro data using the recombinant transporter. We also cloned MRP3 as an inducible transporter in the liver under the cholestatic conditions. Although MRP3 mediates the cellular export of non-conjugated organic anions and glucuronide-conjugates, the substrate specificity of MRP3 is different from that of cMOAT/MRP2 in that glutathione-conjugates are poor substrates for MRP3. It is possible that MRP3 plays an important role under certain pathological conditions in the liver. Since it has been shown that cMOAT/MRP2 and MRP 3 are expressed in the small intestine under physiological conditions, it seems reasonable that these transporters are responsible for the previously reported cellular extrusion of organic anions. We also found that there was MRP activity in the blood-brain and blood-cerebrospinal fluid barriers. RT-PCR resulted in the amplification of MRP1, 5 and 6 from freshly isolated rat cerebral endothelial cells. It has been suggested that there is basolateral localization of MRP1 in the choroid plexus. In conjunction with the P-glycoprotein located on the luminal membrane of cerebral endothelial cells, these transporters play significant roles in restricting the entry of xenobiotics from the circulating blood into the central nervous system. Regulation of the activity of these efflux transporters allows the disposition of drugs to be altered.
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PMID:[Analysis of xenobiotic detoxification system mediated by efflux transporters]. 1059 Jul 10

The emergence of several newly identified members of the ABC transporter family has necessitated the development of antagonists that are able to inhibit more than one transporter. We assessed the ability of the chemosensitizer GF120918 to function as a multispecific antagonist using cytotoxicity assays, rhodamine and calcein efflux assays, and confocal microscopy in cell lines expressing different multidrug resistance transporters. At a concentration of 1 microM in cytotoxicity assays, GF120918 was able to sensitize both S1-B1-20, a subline expressing P-glycoprotein (Pgp), and S1-M1-80, a subline expressing a newly identified mitoxantrone transporter, MXR. GF120918 was ineffective in sensitizing MRP-overexpressing MCF-7 VP-16 cells to etoposide as determined by cytotoxicity studies. In flow cytometry experiments, rhodamine 123 efflux in S1-B1-20 cells was decreased at GF120918 concentrations as low as 25-50 nM, with 250 nM giving complete inhibition of rhodamine efflux. Complete inhibition of rhodamine efflux in mitoxantrone-resistant S1-M1-80 cells required 10 microM. Examination of intracellular mitoxantrone accumulation by confocal microscopy confirmed higher levels of mitoxantrone in S1-B1-20 and S1-M1-80 cells when incubated in the presence of GF120918 than when incubated with mitoxantrone alone. Thus, GF120918 appears to fit the paradigm of a multispecific blocker and is able to block rhodamine and mitoxantrone efflux by the newly identified mitoxantrone transporter. Further studies of this compound should be pursued to determine its feasibility for use in the clinic.
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PMID:Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. 1065 16

Retroviral infection of the Madin-Darby canine kidney (MDCK) renal cell line with human MDR1 cDNA, encoding the P-glycoprotein (P-gp) multidrug resistance efflux pump, induces a major accumulation of the glycosphingolipid (GSL), globotriaosylceramide (Galalpha1-4Galbeta1-4glucosylceramide-Gb(3)), the receptor for the E. coli-derived verotoxin (VT), to effect a approximately million-fold increase in cell sensitivity to VT. The shorter chain fatty acid isoforms of Gb(3) (primarily C16 and C18) are elevated and VT is internalized to the endoplasmic reticulum/nuclear envelope as we have reported for other hypersensitive cell lines. P-gp (but not MRP) inhibitors, e.g. ketoconazole or cyclosporin A (CsA) prevented the increased Gb(3) and VT sensitivity, concomitant with increased vinblastine sensitivity. Gb(3) synthase was not significantly elevated in MDR1-MDCK cells and was not affected by CsA. In MDR1-MDCK cells, synthesis of fluorescent N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-aminocaproyl (NBD)-lactosylceramide (LacCer) and NBD-Gb(3) via NBD-glucosylceramide (GlcCer) from exogenous NBD-C(6)-ceramide, was prevented by CsA. We therefore propose that P-gp can mediate GlcCer translocation across the bilayer, from the cytosolic face of the Golgi to the lumen, to provide increased substrate for the lumenal synthesis of LacCer and subsequently Gb(3). These results provide a molecular mechanism for the observed increased sensitivity of multidrug-resistant tumors to VT and emphasize the potential of verotoxin as an antineoplastic. Two strains (I and II) of MDCK cells, which differ in their glycolipid profile, have been described. The original MDR1-MDCK parental cell was not specified, but the MDR1-MDCK GSL phenotype and glycolipid synthase activities indicate MDCK-I cells. However, the partial drug resistance of MDCK-I cells precludes their being the parental cell. We speculate that the retroviral transfection per se, or the subsequent selection for drug resistance, selected a subpopulation of MDCK-I cells in the parental MDCK-II cell culture and that drug resistance in MDR1-MDCK cells is thus a result of both MDR1 expression and a second, previously unrecognized, component, likely the high level of GlcCer synthesis in these cells.
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PMID:Retroviral transfection of Madin-Darby canine kidney cells with human MDR1 results in a major increase in globotriaosylceramide and 10(5)- to 10(6)-fold increased cell sensitivity to verocytotoxin. Role of p-glycoprotein in glycolipid synthesis. 1069 20


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