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 effect of Toremifene on cell growth in vitro was tested on the R3230AC rat mammary adenocarcinoma as model. Toremifene differed from Tamoxifen in that it did not induce resistance; some cross-resistance was observed in Tamoxifen tolerant tumour cell lines. Toremifene does not influence P-glycoprotein expression in this model and at the levels studied.
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PMID:Toremifene resistance in a rat mammary tumour model. 135 32

The effect of treatment with the antiestrogen Tamoxifen on the distribution and localization of P-glycoprotein was determined by immunohistochemistry in a rat mammary tumour model, the R3230AC. Both in the untreated and the treated tumours, P-glycoprotein is unevenly expressed with numerous negative tumour cells and located predominantly in the cytoplasmic membranes. Administration of Tamoxifen significantly lowers P-glycoprotein content of the tumour studied.
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PMID:Immunohistochemical determination of P-glycoprotein in a rat mammary tumour treated with tamoxifen. 136 Aug 43

The initial benefits of antiestrogen treatment in mammary cancer tend to decrease with time as antiestrogen resistant subpopulations of cancer cells predominate. The role of P-glycoprotein in this phenomenon is not known. In the tumour model investigated, estradiol increased this efflux pump, while prolonged Tamoxifen exposure resulted in cell populations tolerant to the drug and with decreased P-glycoprotein expression. While Tamoxifen resistance is clinically undesirable, selective pressure by this drug may result in cancer cell lines with increased vulnerability to other chemotherapeutic modalities.
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PMID:Decreased P-glycoprotein in a tamoxifen-tolerant breast carcinoma model. 167 18

Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.
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PMID:Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia. 756 1

Drug resistance is a common phenomenon in clinical oncology. In vitro, tamoxifen has been shown to be an effective inhibitor of P-glycoprotein and a modulator of the multidrug resistance phenotype. We have previously shown that vinblastine can be given safely in combination with tamoxifen at doses that may modulate P-glycoprotein activity. In this phase I trial, tamoxifen (150 mg/m2 twice a day) was given with CHOPE (cyclophosphamide/doxorubicin/vincristine/prednisone/etoposide) in order to assess the toxicities of the combination. Resistance to three of these cytotoxic agents (doxorubicin, vincristine, and etoposide) may be mediated by P-glycoprotein. A total of 13 patients were evaluable on this trial, which showed that the maximum tolerated doses of cyclophosphamide and etoposide were 750 and 80 mg/m2, respectively. The dose-limiting toxicity was myelosuppression with 50% of the patients (3/6) treated at this dose level developing febrile neutropenia and 85% (6/7) developing grade 4 neutropenia. Tamoxifen at a dose of 150 mg/m2 twice a day can be given safely with the lymphoma regimen CHOPE at standard doses, but this combination may result in increased myelosuppression.
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PMID:A phase I trial of high-dose oral tamoxifen and CHOPE. 772 Jan 78

Tamoxifen is an anti-oestrogen which is currently being assessed as a prophylactic for women at high risk of breast cancer. Taxoxifen has also been shown to reverse multidrug resistance in P-glycoprotein (P-gp)-expressing cells, although the mechanism of action is unknown. In this study we demonstrate that tamoxifen interacts directly with P-gp. Plasma membranes from P-gp-expressing cells bound [3H]tamoxifen in a specific and saturable fashion. A 180 kDa membrane protein in these membranes, labelled by the affinity analogue tamoxifen aziridine and azidopine, was shown to be P-gp. Tamoxifen reduced the binding of vinblastine and azidopine to P-gp, and tamoxifen increased [3H]vinblastine accumulation in P-gp-expressing cells to levels approaching those in non-P-gp-expressing cells. However, the cellular accumulation of [3H]tamoxifen itself was not influenced by the presence of P-gp. Thus, tamoxifen appears to reverse multidrug resistance by binding to P-gp and inhibiting the transport of cytotoxic drugs, but does not itself appear to be transported by the protein.
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PMID:Interaction of tamoxifen with the multidrug resistance P-glycoprotein. 784 Oct 43

Tamoxifen (TAM), a widely used agent in the hormonal therapy of breast cancer, is also an antagonist of P-glycoprotein (P-gp), a cell surface protein which confers drug resistance to cells. Here we report that in an estrogen receptor-deficient multidrug-resistant subline of MCF-7 human breast carcinoma cells (MCF-7/MDR), but not in the parent drug-sensitive cells (MCF-7/WT), clinically relevant concentrations (1-5 microM) of TAM inhibited the uptake and phosphorylation of ethanolamine and choline. These inhibitory effects resulted in decreased synthesis of the corresponding phospholipids. In view of the known dependence of P-gp function on phosphatidylethanolamine (PtdEtn), inhibition of PtdEtn synthesis may represent an additional mechanism by which TAM inhibits P-gp-mediated drug efflux.
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PMID:Tamoxifen inhibits uptake and metabolism of ethanolamine and choline in multidrug-resistant, but not in drug-sensitive, MCF-7 human breast carcinoma cells. 787 22

In this study for the first time we used an electrophilic analog of tamoxifen, [3H]tamoxifen aziridine, and demonstrated that it covalently and specifically binds to P-glycoprotein in multidrug resistant cells. Tamoxifen and its metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, were potent inhibitors of [3H]tamoxifen aziridine binding to P-glycoprotein with 4-hydroxytamoxifen > tamoxifen > N-desmethyltamoxifen. The multidrug resistance-related drugs inhibited [3H]tamoxifen aziridine binding with vinblastine > vincristine > doxorubicin > actinomycin D, while colchicine enhanced the binding. Moreover, the multidrug resistance modulators verapamil, nicardipine, diltiazem, prenylamine, cyclosporin A, FK506, dibucaine, reserpine, monensin and progesterone were all potent inhibitors of [3H]tamoxifen aziridine binding to P-glycoprotein. Our data provide the first evidence that [3H]tamoxifen aziridine directly binds to P-glycoprotein and interacts with the binding sites for multidrug resistance-related drugs and modulators.
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PMID:Tamoxifen aziridine, a novel affinity probe for P-glycoprotein in multidrug resistant cells. 791 4

1. We have studied the permeation and pharmacological properties of a recently described volume-activated, calcium-insensitive, small-conductance Cl(-)-channel in endothelial cells from human umbilical vein. 2. The relative permeability for various anions was I- > Cl- approximately Br- > F- > gluconate- (1.63 +/- 0.36: 1:0.95 +/- 0.16:0.46 +/- 0.04:0.19 +/- 0.07, n = 10). 3. 5-Nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) induced a fast and reversible block of the current (Ki = 29 mumol l-1). 4. Extracellular ATP induced a low-affinity block of the current, that showed a small voltage-dependence (K1 = 4.9 mmol l-1 at +80 mV and K1 = 8.2 mmol l-1 at -80 mV). 5. Extracellularly applied arachidonic acid (10 mumol l-1) irreversibly blocked the current in 5 out of 9 cells. This block seems to be non-specific, because other ionic currents, e.g. inwardly rectifying K+ currents, were blocked as well. 6. Tamoxifen induced a high affinity block of the current (K1 = 2.9 mumol l-1). Block and reversal of block were however much slower than with NPPB. 7. Cytotoxic compounds, which are substrates of the P-glycoprotein multidrug transporter, loaded into endothelial cells via the patch pipette, exerted only minor effects on the volume-activated current. Vinblastine and colcemid did not affect the volume-activated current, whereas daunomycin and vincristine induced a slow 'run-down' of the current. 8. The similarity between permeation and pharmacological properties of volume-activated Cl--currents in endothelial cells and those in many other cell types may suggest that they all belong to the same family of volume-activated small-conductance Cl--channels. Evidence that they belong to the class of P-glycoprotein associated Cl--channels is however only marginal, whereas their biophysical characteristics differ significantly from those of the CIC-2 volume-activated Cl--channels.
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PMID:Permeation properties and modulation of volume-activated Cl(-)-currents in human endothelial cells. 795 63

P-glycoprotein, an active transporter that pumps a diverse range of hydrophobic compounds out of cells, has recently been proposed to function as, or regulate, a volume-activated, anion-selective channel (Valverde, M.A., Diaz, M., Sepulveda, F. V., Gill, D. R., Hyde, S. C., and Higgins, C. F. (1992) Nature 355, 830-833). In this study a number of compounds known to inhibit P-glycoprotein-mediated drug pumping were tested for their effect on the osmotically activated release from HeLa cells of I-, a known substrate of volume-activated anion channels, and taurine, a sulfonic amino acid that serves as an important organic osmolyte in many cell-types. Tamoxifen, 4-iodotamoxifen, and pyrrolidino-4-iodotamoxifen (idoxifene) were potent blockers of osmotically activated I- and taurine efflux. Other known P-glycoprotein inhibitors (verapamil, cyclosporin A, pimozide, trifluoperazine, ICI 164, and ICI 182) were less effective. For all compounds tested the effect on taurine release was the same as that on I- release, consistent with the hypothesis that swelling-activated taurine release is via anion-selective channels. There was no positive correlation between the effect of the inhibitors on osmotically activated solute release and their effect on P-glycoprotein-mediated drug transport. In contrast, there was a strong positive correlation between the IC50 values for the effect of the inhibitors on volume-activated solute release and those for their effect on calmodulin. These data raise doubts as to whether the effect of P-glycoprotein inhibitors on volume-activated channels is a consequence of their interaction with P-glycoprotein and indicate a possible role for calmodulin, or a cell component having at least some physical similarities, in controlling channel activity.
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PMID:Inhibition of volume-activated I- and taurine efflux from HeLa cells by P-glycoprotein blockers correlates with calmodulin inhibition. 796 17


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