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)

The major limitation of treatment with antimetabolite drugs is that they produce resistant clones both in vitro and in patients who either do not respond to treatment or relapse soon after response has been documented. To better understand the phenomenon of cross-resistance, we developed seven CEM/ara-C-resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from 4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using this model, we determined IC50 concentrations to several chemotherapeutic agents and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2) proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related protein (MRP). The cell viability assays showed that these clones were cross-resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to 8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x 10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from 1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2 protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10 microM ara-C for 48 hours showed increased p53 protein expression in most of these lines. No increase in bcl-2 protein expression was seen in the wt cell line after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara-C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl-2 protein after treatment with 1 microM ara-C, but not after 10 microM. This alteration may lead to resistance to apoptosis and enhanced cell survival. The ratio of bcl-2 to p53 was increased significantly in these three clones, thus favoring an anti-apoptotic drive. All of the cell lines examined were negative for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for MRP functional activity. However, three ara-C resistant cell clones, CEM/ara-C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and functional activity. It is apparent that selection for ara-C resistance confers cross-resistance to many other classes of drugs and gamma radiation, probably due to bcl-2 protein overexpression or P-gp and MRP expression, as independent mechanisms.
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PMID:Cytosine arabinoside (ara-C) resistance confers cross-resistance or collateral sensitivity to other classes of anti-leukemic drugs. 1076 46

The role of multidrug resistance (MDR) and p53 functional status in the treatment of paediatric rhabdomyosarcoma is unclear. We have characterized a panel of seven human rhabdomyosarcoma cell lines for MDR and p53 phenotype. None of the cell lines had P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) detectable by Western blotting, whereas immunohistochemistry suggested that very low levels of MDR proteins may be present in some of the lines. RT-PCR studies indicated that mdr-1, mrp-1 and Irp mRNA was present in 5/7, 7/7 and 5/7 lines respectively. The function of p53 is compromised in six of the lines, either through mutation of the p53 gene or by overexpression of mdm-2. The sensitivity of many of the cell lines to vincristine could be modulated above 2-fold and as high as 16-fold using two modulating agents, PSC833 and VX710 (with VX710 being a significantly more potent modulator of the rhabdomyosarcoma lines). PSC833 also increased vincristine accumulation in all of the lines from 1.2- to 2.2-fold. These results suggest that some of these cell lines have low levels of multidrug resistance. The level of MDR proteins is very low and therefore difficult to detect, but may be sufficient to confer low-level, but clinically relevant, resistance to some cytotoxic agents, especially vincristine. These cell lines will therefore provide a suitable model to test new strategies in treatment and for further understanding relationships between protein expression and drug resistance.
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PMID:Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines. 1091 49

The 2 clones, LoVo 5 and LoVo 7, derived from untreated LoVo WT human colon adenocarcinoma cells and exhibiting different sensitivity to doxorubicin (DOX), were compared in order to identify possible determinants of intrinsic drug resistance. A multidrug resistant variant cell line, selected from LoVo WT cells by continuous exposure to DOX (LoVo DX), was also included in the study. Analysis of the expression and organization of cytoskeletal elements by flow cytometry and fluorescence microscopy evidenced a positive correlation between vimentin expression and DOX resistance in LoVo 7 and LoVo DX cells, whereas differences in actin, tubulin or cytokeratin did not seem to relate to drug response. The expression and localization of different drug transporters commonly implicated in drug resistance, i.e., the MDR1 gene product P-glycoprotein (P-gp), the multidrug resistance-related protein MRP and the lung resistance-related protein LRP were also investigated by means of flow cytometry and fluorescence microscopy, following labeling with specific monoclonal antibodies. Surface expression of P-gp was only detected in LoVo DX cells, which also exhibited increased MRP and LRP protein levels. However, significant amounts of P-gp were found at intracellular sites in the intrinsically resistant LoVo 7 clone. Modulation of P-gp function by cyclosporin A was found to alter DOX accumulation and efflux in LoVo 7 cells, indicating that intracellular P-gp plays a functional role in drug trafficking and suggesting possible implications in determining the intrinsic resistance displayed by this clone.
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PMID:Intracellular P-glycoprotein expression is associated with the intrinsic multidrug resistance phenotype in human colon adenocarcinoma cells. 1092 53

Melanoma cells exhibit, both in vivo and in vitro, intrinsic drug resistance to various chemotherapeutic agents. Cultured human melanoma cells (M14) intrinsically express significant amounts of multidrug resistance-related protein (MRP1) and P-glycoprotein (P-gp) in the Golgi apparatus, but do not express these drug transporters on the plasma membrane. A panel of multidrug resistant (MDR) melanoma cell lines (M14Dx), showing different degrees of resistance to doxorubicin (DOX), were isolated. In M14Dx lines, the appearance of surface P-gp, but not of MRP1 or lung resistance related protein (LRP), occurred in cells grown in the presence of DOX concentrations higher than 60 nM. Furthermore, P-gp levels appeared to be dose-dependent. Flow cytometry, laser scanning confocal microscopy and cytotoxicity studies demonstrated that the activity of the drug extrusion system was related to both surface P-gp expression and resistance to DOX. In conclusion, P-gp, but not MRP1 or LRP, might play a pivotal role in the pharmacologically-induced MDR phenotype of melanoma cells.
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PMID:Induction of P-glycoprotein expression on the plasma membrane of human melanoma cells. 1095 45

Grepafloxacin and levofloxacin transport by Caco-2 cell monolayers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [(14)C]grepafloxacin and [(14)C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direction. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [(14)C]grepafloxacin were comparable to those of cyclosporin A alone, indicating that the transport of grepafloxacin across the apical membrane was mainly mediated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [(14)C]levofloxacin in the presence of cyclosporin A was decreased by unlabeled levofloxacin, grepafloxacin, and enoxacin, accompanied by significantly increased cellular accumulation. The organic cation cimetidine, organic anion p-aminohippurate, and the multidrug resistance-related protein (MRP) modulator probenecid did not affect the transcellular transport of [(14)C]grepafloxacin or [(14)C]levofloxacin in the presence of cyclosporin A. The basolateral-to-apical transcellular transport of levofloxacin in the presence of cyclosporin A showed concentration-dependent saturation with an apparent Michaelis constant of 5.6 mM. In conclusion, these results suggested that basolateral-to-apical flux of quinolones was mediated by P-glycoprotein and a specific transport system distinct from organic cation and anion transporters and MRP.
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PMID:Secretory mechanisms of grepafloxacin and levofloxacin in the human intestinal cell line caco-2. 1099 2

P-glycoprotein (P-gp) and multidrug resistance related protein (MRP) overexpression is often responsible of the development of multidrug resistance in cancer therapy. These proteins are also expressed in normal tissues, where their physiological role is related to the extrusion of endogenous toxins or to secretory function in liver and kidney. The LLC-PK1 cell line is derived from normal pig proximal renal tubule and physiologically expresses low levels of P-gp and MRP. A resistant cell line (LLC-PK1/ADR) has been established in our laboratory by chronic exposure to increasing doses of doxorubicin. Cytofluorimetric analysis of P-gp and MRP expression performed by C219 and MRPm6 immunofluorescence detection showed that these cells overexpress P-gp but not MRP. The uptake of doxorubicin and rhodamine 123 has been quantified in LLC-PK1 and LLC-PK1/ADR cells and compared with data obtained using other tumor cell lines commonly used as reference for studying P-gp or MRP overexpression. P388 sensitive cells and its resistant counterpart P388/ADR cells, which overexpress P-gp and PANC-1 cells, which express high levels of MRP were used. A lower fluorescence intensity was evident with both doxorubicin and rhodamine 123 in LLC-PK1/ADR as well as in P388/ADR cells, that overexpresses P-gp, in comparison with the parental lines. The uptake was increased by a pretreatment with verapamil. Verapamil was completely ineffective on PANC-1 cells, confirming a selective effect of this inhibitor on P-gp. Propidium iodide staining, performed after doxorubicin treatment, confirmed a higher cytotoxicity of the antineoplastic drug in the LLC-PK1 cells compared with the resistant counterpart.
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PMID:Cytofluorimetric analysis of a renal tubular cell line and its resistant counterpart. 1113 40

Intestinal drug efflux mediated by P-glycoprotein and other ABC transporters is widely accepted as a reason for low or variable oral absorption. However, little is known about species and regional differences in P-glycoprotein so the functional and predictive relevance of observations made in cell models such as Caco-2 is uncertain. The aim of this study was to define the kinetics of drug efflux in rat and human intestinal tissues in vitro using the "reference" substrates digoxin and vinblastine. The expression and functional role of other ABC transporters in the transport of these compounds was also investigated. Saturable, verapamil-sensitive efflux of digoxin was observed in all intestinal regions. Apparent affinity of the efflux process varied within a relatively narrow range (50-92 microM), increasing in rat from small to large intestine. In contrast, maximal transporter activity varied over a 4- to 5-fold range with ileum > jejunum > colon. Similar regional differences in efflux were also observed with vinblastine. Maximal efflux levels were similar in Caco-2 and ileum for both substrates, suggesting that Caco-2 may quantitatively predict small intestinal drug efflux. Digoxin efflux kinetics was virtually identical in rat and human colon. Inhibitor studies showed that digoxin and vinblastine efflux in intestinal tissues was mediated by P-glycoprotein, although a minor component could be attributed to multidrug resistance-related protein (MRP)-like transporters in Caco-2. This study has analyzed the differential functional expression of drug efflux along the gastrointestinal tract. Such data will be critical in developing predictive models of P-glycoprotein-mediated efflux using information gathered from in vitro systems.
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PMID:Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. 1116 Jun 47

The purpose of this study was to retrospectively study 48 patients with infiltrating ductal breast cancer to evaluate the relationship between the degree of accumulation of technetium-99m methoxyisobutylisonitrile (Tc-MIBI) and P-glycoprotein (Pgp) or multidrug resistance-related protein (MRP) expression in breast cancer tissues. Before surgery or biopsy, all 48 patients underwent scintimammography started 10 min after the injection of Tc-MIBI. Tumor:background (T:B) ratios were calculated from the Tc-MIBI scintimammography. Immunohistochemical analysis was performed on the pathological specimens of the 48 breast tumors to determine Pgp and MRP expression. According to the results of immunohistochemical analysis, the 48 breast cancers were separated into four groups: (a) group 1, 12 cancers with both positive Pgp expression and positive MRP expression; (b) group 2, 12 cancers with positive Pgp expression and negative MRP expression; (c) group 3, 12 cancers with negative Pgp expression and positive MRP expression; and (d) group 4, 12 cancers with both negative Pgp expression and negative MRP expression. Among the four groups, the T:B ratio was lowest in group 1 (1.13+/-0.10) and highest in group 4 (2.17+/-0.14), respectively (P < 0.05). The T:B ratios of groups 2 (1.30+/-0.25) and 3 (1.32+/-0.26) were between those of groups 1 and 4. Our data confirmed that Tc-MIBI scintimammography is useful for determining Pgp and MRP expression in patients with breast cancers.
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PMID:P-Glycoprotein and multidrug resistance-related protein expressions in relation to technetium-99m methoxyisobutylisonitrile scintimammography findings. 1180 18

The purpose of the present study was to predict the response of malignant lymphomas (MLs) to chemotherapy using technetium-99m methoxyisobutylisonitrile (Tc-MIBI) scan and to compare it with the predictive ability of P-glycoprotein (P-gp) expression, multidrug resistance-related protein (MRP) expression and other prognosis factors. Twenty-five ML patients were enrolled in this study prior to initiation of chemotherapy. Images were obtained 10 min after intravenous injection of Tc-MIBI, interpreted visually and the tumour-to-background (T/B) ratios calculated. Immunohistochemical analyses were performed on sections of the biopsy specimens to determine P-gp and MRP expression. Chemotherapy response was evaluated in the first 1-2 years after completion of chemotherapy. The mean T/B ratio of the 15 patients with a good response (3.3 +/- 0.6) was significantly higher than that of the 10 patients with a poor response (1.2 +/- 0.1). All 15 patients with a good chemotherapy response had positive Tc-MIBI scan results and negative P-gp and MRP expression. All 10 patients with a poor response had negative Tc-MIBI scan results and either positive P-gp or MRP expression. Other prognosis factors showed no significant difference in the incidence of good and poor responses. Tc-MIBI scan results represent P-gp or MRP expression more accurately than other prognosis factors and predict the chemotherapy response in ML patients.
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PMID:Technetium-99m-sestamethoxyisobutylisonitrile scan as a predictor of chemotherapy response in malignant lymphomas compared with P-glycoprotein expression, multidrug resistance-related protein expression and other prognosis factors. 1138 Apr 1

The aim of this study was to investigate the relationships among technetium-99m tetrofosmin (Tc-TF) accumulation in untreated small cell lung cancer (SCLC), the expression of P-glycoprotein (Pgp) and multidrug resistance related protein-1 (MRP1), and the response to chemotherapy in patients with untreated SCLC. Thirty patients with SCLC were studied with chest scintigraphy 15 to 30 min after intravenous injection of Tc-TF before chemotherapeutic induction. Tc-TF chest scans were interpreted both visually and quantitatively. The response to chemotherapy was evaluated upon completion of chemotherapy. Immunohistochemical analyses were performed on multiple non-consecutive sections of biopsy specimens to detect Pgp and MRP1 expression. Fifteen patients with good response to chemotherapy had a significantly higher incidence (100.0%) of positive Tc-TF chest single photon emission computed tomography (SPECT) findings and negative Pgp or MPR expression than 15 patients with poor response (20%) (P<0.05). The tumor/background (T/B) ratios were 1.8+/-0.3 and 1.2+/-0.3 for patients with good response and poor response, respectively (P<0.05). However, other prognostic factors (performance status, tumor size and stage) were not significantly related to Tc-TF chest scan findings and response to chemotherapy. Tc-TF chest scintigraphy correlated well with Pgp or MRP1 expression and accurately predicted the response to chemotherapy in patients with SCLC.
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PMID:To predict chemotherapy response using technetium-99m tetrofosmin and compare with p-glycoprotein and multidrug resistance related protein-1 expression in patients with untreated small cell lung cancer. 1143 Nov 7


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