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)

The characteristics and clinical efficacies of new hormonal drugs and new treatment methods for breast cancer using tamoxifen (TAM) were described. The new anti-estrogens, such as trioxifen, toremifene and droloxifen, have equal or better clinical efficacy than TAM. They showed a high response rate in postmenopausal patients with no previous treatment or estrogen receptor positive tumors. They were occasionally effective for patients who relapsed after TAM treatment. Pure anti-estrogen ICI 164, 384, with fewer estrogenic agonistic properties than TAM, and anti-estrogen TAT-59, which has been developed in Japan, are under clinical investigation. Luteinizing hormone-releasing hormone agonists, such as leuprolide, buserelin, triptrelin and goserelin, are available for premenopausal patients, and showed a 37% response rate on average. The pure aromatase inhibitors, such as 4-hydroxyandrostenedione and CGS 16, 949 A, are available for postmenopausal patients, and showed 30% and 17% response rates on average, respectively. The new pure aromatase inhibitor ZD-1033 is also under clinical investigation. TAM or toremifene as well as the calcium antagonist verapamil were proved to overcome the multiple anticancer drug resistance caused by P-glycoprotein. Clinical studies for breast cancer using high-dose TAM as a potential modulator of drug resistance have already been started in Europe and the United States. Chemoprevention of breast cancer using TAM, which started in the U.S., was described.
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PMID:[Recent development of endocrine treatment for breast cancer--new drugs and new treatment methods using tamoxifen]. 825 41

In this paper, we report that an archaebacterium, Haloferax volcanii, cultured in medium containing a large excess of amino acids showed very low levels of rhodamine 123 (RH123), which is a potent substrate for P-glycoprotein and the bacterial multidrug efflux transporter. This low level involved the active efflux of RH123 from the cells. The level of intracellular RH123 was increased and the efflux inhibited by the Ca2+-channel antagonist verapamil and also by various anti-cancer drugs. The efflux transporter was suggested to be ATP-driven. We have previously selected a mutant of H. volcanii with resistance to doxorubicin, by repeatedly culturing cells in 1.5 microM doxorubicin [Miyauchi, Komatsubara and Kamo (1992) Biochim. Biophys. Acta 1110, 144-150]. The acquisition of resistance to doxorubicin involves the active expulsion of lipophilic drugs such as RH123 and doxorubicin. It is notable that the drug spectrum and ATP-dependency of the amino acid-induced efflux transporter resemble those of the efflux transporter induced by doxorubicin.
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PMID:Rhodamine 123 efflux transporter in Haloferax volcanii is induced when cultured under 'metabolic stress' by amino acids: the efflux system resembles that in a doxorubicin-resistant mutant. 866 Mar 7

P-glycoprotein (Pgp), a product of the human MDR1 gene, is a member of the ABC superfamily of transporters responsible for the trafficking of biologically active substances across the membrane. In tumors, Pgp is associated with multidrug resistance (MDR), the phenomenon characterized by the ability of cells to efflux structurally diverse lipophilic compounds. It has been demonstrated that Pgp is also expressed on various types of normal human tissues and cells, including hematopoietic stem cells, T, B, and natural killer (NK) cells. The normal physiologic function of Pgp in immune cells is unclear. In this study, we used highly specific and nontoxic monoclonal antibodies (mAbs) against external epitopes of Pgp (mAb UIC2, its monovalent Fab fragments, and mAb MRK16) to inhibit Pgp-mediated efflux and investigate a possible role of Pgp in activated T lymphocytes. We found that the treatment of phytohemagglutinin (PHA)-stimulated peripheral blood leukocytes (PBL) with these mAbs resulted in a significant reduction of interleukin-2 (IL-2) levels in the culture. Early activation events, as measured by intracellular calcium flux, expression of the CD69 early activation marker, and expression of IL-2 mRNA, were not affected by anti-Pgp mAbs. These results suggest that the Pgp efflux pump may be involved in the transport of IL-2 in T lymphocytes.
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PMID:Monoclonal antibodies against P-glycoprotein, an MDR1 gene product, inhibit interleukin-2 release from PHA-activated lymphocytes. 876 2

1. The whole-cell patch clamp technique was used to investigate the swelling-activated currents in bovine non-pigmented ciliary epithelial (NPCE) cells. 2. Exposure to hypotonic solution activated a current that was blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). The I-V relationship was shifted in the direction expected for a Cl- current when the external Cl- was replaced by gluconate (permeability ratio P(gluconate)/PCl = 0.17). The inhibition of the current evoked by voltage clamp steps of +80 mV yielded an IC50 for NPPB of 13.4 microM. 3. The current was found to be dependent on ATP. With ATP in the patch pipette the current could be repeatedly activated by exposure to hypotonic solution but when ATP was omitted the current ran down with time. 4. The development of this current was associated with visible cell swelling and inhibitors of regulatory volume decrease in these cells, e.g. tamoxifen, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulphonic acid (SITS) and 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), also inhibited this current. 5. The volume-activated current was additionally blocked by NPPB, verapamil, quinidine and dideoxyforskolin. 6. The current was independent of external calcium and exhibited slight outward rectification and time-dependent inactivation at strong depolarizing potentials. 7. Disrupting the cytoskeleton and microtubules with cytochalasin B and colchicine had no effect on the activation of the Cl- current. 8. An antibody (C219) to the MDR1 gene product, P-glycoprotein, caused a functional block of the swelling-activated Cl- current when added to the patch pipette. 9. Immunofluorescence studies using the monoclonal antibodies C219 and JSB-1 demonstrated the presence of P-glycoprotein in the ciliary epithelial cells. The immunofluorescence was stronger on the non-pigmented than on the pigmented cells. 10. It is concluded that swelling in NPCE cells activates a Ca(2+)-independent, ATP-dependent Cl- current and that the activity of this current is associated with P-glycoprotein. 11. It is suggested that this Cl- current contributes to regulatory volume decrease and may participate in the secretory activity of these cells.
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PMID:P-glycoprotein regulates a volume-activated chloride current in bovine non-pigmented ciliary epithelial cells. 881 8

Effects of xanthine derivatives (pentoxifylline, caffeine, theophylline, 1-methyl-3-isobutylxanthine) on P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cell subline were studied. From the applied xanthines only PTX was found to reverse the vincristine resistance of the above cells. Moreover, only PTX, but not other xanthine, increased the accumulation of [3H]vincristine by L1210/VCR cells. Thus it may be concluded that PTX-induced reversal of vincristine resistance could not be explained from the point of known pharmacological effects of PTX that are common for other xanthines such as inhibition of phosphodiesterase activity, calcium mobilizing effect, inhibition of tumor necrosis factor alpha (TNF), etc.
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PMID:Overcoming of P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cells could be induced by pentoxifyline but not by theophylline and caffeine. 884 53

The detection of multidrug resistance (MDR) in clinical samples is still a topic for discussion. One method, proven extremely useful for detection of membrane proteins in patients with hematological malignancies is the flow cytometrical analysis of individual tumor cells. Recently an assay was described based on the labeling of the P-glycoprotein (P-gp) with the monoclonal antibody MRK16, combined with detection of active daunorubicin (DNR) extrusion. In order to improve the specificity of the assay, on line with the results obtained by Wall et al., we exploited staining with Fluo-3. Both assays prove to be able to discriminate between drug-resistant and drug-sensitive cells. A major drawback of labeling with Fluo-3 in combination with the monoclonal antibody MRK16 is the important overlap of emission spectra of both fluorochromes. Moreover, using Fluo-3 for the detection of MDR might be complicated by the fact that differences in fluorescence intensities are not solely dependent on the presence of P-gp, but also on the activity of cytosolic esterases and the intracellular calcium concentration. Combination of the detection of structural and functional aspects of the MDR-associated protein may lead to a more precise detection of the MDR-positive patient.
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PMID:Comparison of daunorubicin and Fluo-3 for detection of multidrug resistance in human tumor cells. 904 67

Iodide efflux, an index of anion permeability, has been monitored in cultured rat brain endothelial cells. Following hypotonicity-induced swelling, large, rapid increases in permeability occur, the extent of these increases depending on the degree of hypotonicity. Such large responses are not observed with rat aortic endothelial cells. Results of anion substitution experiments suggest that iodide efflux is via a chloride channel rather than an exchanger. The efflux increase is blocked by NPPB (100 microM) but not by DIDS or DPC at 100 microM. It is dependent on intracellular ATP but unaffected by removal of external calcium. Increasing internal calcium using A23187 does not produce a change in efflux, but depletion of calcium reduces or eliminates the response to hypotonicity. The response is reduced by pimozide (2-50 microM) that inhibits the actions of calmodulin and by pBPB (10 microM) that affects phospholipase A2 activity. It is eliminated by 5-lipoxygenase inhibitors (L-656,224 and ETH615, 10 microM) but is unaffected by cyclo-oxygenase inhibitors (indomethacin and piroxicam, 1-100 microM). It is blocked by some modulators of P-glycoprotein activity, e.g., verapamil (100 microM), tamoxifen (50 microM), and progesterone (100 microM) but not by others, e,g., forskolin (40 microM), dideoxyforskolin (40 microM), quinidine (100 microM) and cyclosporin A (10 microM).
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PMID:Hypotonicity-induced changes in anion permeability of cultured rat brain endothelial cells. 910 87

The unidirectional brain-to-blood transport system for corticotropin-releasing hormone (CRH) across the blood-brain barrier could be instrumental in the homeostasis of central CRH. To characterize this system, the intracerebroventricular injection of 125I-CRH was used in mice. CRH was rapidly transported out of the brain with a half-time disappearance (t1/2) of 15 min, much faster than albumin (t1/2 = 50 min). Kinetic analysis revealed a saturable component with a low maximum velocity (apaproximately 0.020 nmol x min(-1) x brain(-1)) and low capacity (Michaelis constant approximately 1.4 nmol/brain). Transport was inhibited by verapamil, ouabain, and colchicine but not by cyclosporin. Transport was increased by corticosterone and inhibited by tumor necrosis factor-alpha and beta-endorphin. These results suggest that the specific unidirectional brain-to-blood transport system for CRH is dependent on energy and calcium channels, involves microtubules, is independent of the P-glycoprotein transporter, and is acutely modulated by adrenal steroids, cytokines, and endogenous opiates. This suggests its participation in the control of the stress response.
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PMID:Acute modulation of active carrier-mediated brain-to-blood transport of corticotropin-releasing hormone. 912 40

P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are members of the superfamily of ATP-binding cassette transporter proteins. Because the ATP-dependent export system has been implicated in the release of leukotriene C4 (LTC4), we examined the roles of P-gp and MRP in the release of LTC4 from normal murine mast cells (MC-9). We have previously shown that MC-9 cells express P-gp at the level of protein and mRNA. In the present study, MRP expression in MC-9 cells was examined at the protein level by anti-MRP Ab, using flow cytometry and at the level of mRNA by PCR and Northern blot analyses. MC-9 cells were stimulated with calcium ionophore A23187 for 15 min in the presence or the absence of various concentrations of cyclosporin A (CsA) and its nonimmunosuppressive analogue CsA-1, which are known to inhibit P-gp efflux function, or in the presence or the absence of probenecid, an organic ion transport inhibitor that appears to inhibit MRP-mediated transport function. Culture supernatants were collected, and LTC4 was measured by ELISA assay. CsA and CsA-1 had no effect on LTC4 secretion from MC-9 cells, suggesting that P-gp is not involved in LTC4 release from MC-9 cells. In contrast, probenecid, in a concentration-dependent manner, inhibited LTC4 secretion from MC-9 cells without inhibiting its synthesis. However, MC-9 lacked MRP at both the protein and mRNA levels. These data suggest that LTC4 is secreted by normal mast cells by a probenecid-sensitive mechanism that is independent of MRP.
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PMID:Leukotriene C4 secretion from normal murine mast cells by a probenecid-sensitive and multidrug resistance-associated protein-independent mechanism. 914 9

We have studied the effects of a novel derivative of apovincaminic acid ester, VA-033, on the resistance of tumors to chemotherapeutic agents. VA-033 increased the sensitivity of drug-resistant cell lines (P388/VCR, P388/ADM, AD10, and K562/ADM) to adriamycin or vincristine. The potency of VA-033 was stronger than verapamil. The drug lengthened the survival time of the P388/VCR-implanted mice treated with vincristine. VA-033 increased the intracellular accumulation of vincristine in the tumor cells, and the photolabeling of P-glycoprotein by [3H]azidopine was inhibited by VA-033. VA-033 showed a slight inhibitory effect on the L-type Ca2+ current in the ventricular myocytes, and had less effect on the cardiovascular parameters such as blood pressure, contractile force and atrio-ventricular conduction time than verapamil when administered systemically in the dog. These results suggest that VA-033 may become a beneficial compound as a modifier to the neoplastic cell resistant to multidrugs.
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PMID:Overcoming of multidrug resistance by VA-033, a novel derivative of apovincaminic acid ester. 920 May 66


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