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 role of P-glycoprotein in mediating the drug-resistance phenotype in multidrug resistant cells is now well documented. It is thought to function as an energy-dependent drug-efflux pump of broad specificity. Structurally, P-glycoprotein is an internally duplicated molecule containing two large multi-spanning transmembrane domains and two cytoplasmic ATP binding domains. In this report we demonstrate that monoclonal antibodies C219, C494, and C32 directed against short linear regions of the P-glycoprotein molecule inhibit ATP binding to P-glycoprotein in vitro. We also provide direct evidence that both predicted ATP-binding domains bind ATP and that there is co-operativity between the two sites. In addition, the capacity of P-glycoprotein to bind the calcium channel blocker, azidopine, is inhibited differentially by the antibodies. These observations are the first evidence linking specific perturbations of the P-glycoprotein molecule with ATP and drug binding.
J Cell Physiol 1991 Sep
PMID:Modulation of ATP and drug binding by monoclonal antibodies against P-glycoprotein. 168 Aug 71

Chemotherapy plays an important role in therapy for patients with extraocular and metastatic retinoblastoma. The authors used chemotherapy for management of selected patients with uncontrolled intraocular tumors or tumors larger and more posteriorly located than those conventionally treated with local cryotherapy or photocoagulation. Rapid regrowth of some tumors after an initial excellent chemotherapy response led us to investigate the hypothesis that failure of treatment is caused by P-glycoprotein-related multidrug resistance. By using a sensitive immunoperoxidase method, increased P-glycoprotein was detected in five multidrug-resistant and two selectively plant alkaloid-resistant retinoblastoma cell lines and in the intraocular and metastatic tumors from which they were derived. In four chemotherapy-treated cases, increased P-glycoprotein in the tumor samples correlated with clinically relevant drug resistance. None of the four chemosensitive tumor cell lines had increased P-glycoprotein expression. Continuous surveillance of P-glycoprotein levels in metastatic retinoblastoma may be a useful guide to drug therapy.
Ophthalmology 1991 Sep
PMID:Multidrug-resistant phenotype in retinoblastoma correlates with P-glycoprotein expression. 168 62

P-glycoprotein is a transmembrane protein with increased drug efflux from resistant cells, which is encoded by the MDR1 gene. An overexpression of P-glycoprotein has been reported to correlate with the degree of resistance to anticancer agents, especially to adriamycin. In this study, the expression of P-glycoprotein was analyzed immunohistochemically by using a monoclonal antibody, MRK16 against P-glycoprotein in 18 fresh human tumors. The expression of P-glycoprotein was detected in eight (44 per cent) tumor specimens out of 18 patients. Although six (75.0 per cent) of the 8 P-glycoprotein positive tumors were resistant to adriamycin, the other two tumors showed clinical responses. Furthermore, five (50.0 per cent) of the 10 P-glycoprotein negative tumors exhibited positive clinical responses. These results suggest that P-glycoprotein expression may not be a useful marker to predict intrinsic resistance to adriamycin in fresh human tumors.
Jpn J Surg 1991 Sep
PMID:Clinical significance of P-glycoprotein expression analyzed by immunohistochemical staining in cancer tissues. 168 1

Neuroblastoma remains a significant problem in pediatric oncology. Recently a "multidrug-resistance" gene that may cause cells to become resistant to various chemotherapeutic agents has been cloned. The gene encodes the high-molecular-weight plasma membrane protein known as P-glycoprotein. To study the expression of this gene in cells exhibiting the multidrug-resistant phenotype, a panel of sublines selected with several different natural product drugs was established. The drug-sensitive parental BE(2)-C cells were clonally isolated from the human neuroblastoma SK-N-BE(2) line and exhibit a 150-fold increase in the copy number of the N-myc protooncogene. Sublines were selected by stepwise increases in the concentration of actinomycin-D, doxorubicin, vincristine, or colchicine. Gene amplification was assessed using Southern analysis, and RNA levels were determined by Northern and dot-blot analysis. Western blotting was used to determine protein levels. N-myc amplification and expression were simultaneously determined to assess possible alterations associated with development of multidrug resistance. Amplified P-glycoprotein-encoding genes were not seen in control lines but were clearly present in those that had undergone exposure to each of the chemical agents. Similarly, steady-state messenger RNA and protein levels were greatly increased in the drug-resistant sublines. We conclude that human neuroblastoma cells can acquire the multidrug-resistant phenotype after exposure to various chemotherapeutic agents.
J Pediatr Surg 1991 Sep
PMID:Multidrug resistance in human neuroblastoma cells. 171 82

Overexpression of P-glycoprotein may cause increased efflux of a variety of anticancer drugs (ACD) leading to multidrug resistance (MDR) of tumor cells. Two sublines of murine monocytic leukemia P388 cells were used, one parental (Par-P388) and one multidrug resistant (MDR-P388). In cell growth inhibition assays in vitro, the Par-P388 cells showed a normal sensitivity to daunomycin (DAU) while the MDR-P388 cells were 200-fold resistant. In cellular fluorescence assays, DAU retention in MDR-P388 cells reached only 5% of the level achieved in Par-P388 cells. This cell line pair was used to compare the nonimmunosuppressive cyclosporin analog PSC 833 with several resistance-modifying agents (RMAs) for their in vitro chemosensitizing activity and for their restoration of DAU retention. PSC 833 sensitized the MDR-P388 cells 60- and 140-fold when used at 0.1 and 0.3 micrograms/ml (0.08 and 0.25 microM), respectively, a complete restoration of sensitivity being obtained at 1.0 micrograms/ml PSC 833. Similarly as little as 0.1 micrograms/ml (0.08 microM) PSC 833 was sufficient to restore intracellular DAU retention to 60% of the level found in Par-P388 cells, a 3-fold higher concentration restoring virtually the whole DAU retention. For both these activities, PSC 833 was at least one order of magnitude more active than CsA, which was itself an order of magnitude stronger than verapamil, another RMA already used in clinic. Since PSC 833 had no effect on the PAR-P388 cells, neither on chemosensitization nor on drug retention, it is assumed that it acts on the P-glycoprotein, which is highly expressed on the membrane of the MDR-P388 cells, by inhibiting the function of the P-glycoprotein pump and thus restoring a normal ACD-sensitivity of the MDR-P388 cells.
Exp Cell Res 1991 Sep
PMID:Restoration of daunomycin retention in multidrug-resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive cyclosporin derivative. 187 70

Reversal of the drug resistance phenotype by the use of agents which induce cell differentiation offers an experimental approach to the study of chemoresistance. In numerous in vitro models, alpha-interferon (alpha-IFN) has been shown to induce phenotypical changes and to modulate the growth of cancer cells. The aim of the present study was to define the effect of alpha-IFN on the Adriamycin sensitivity of the human colon adenocarcinoma cell line, LoVo, and its Adriamycin-resistant variant, LoVo/DX. Pretreatment of LoVo/DX cells with 500 units/ml of alpha-IFN increased sensitivity to low doses of Adriamycin. Similar treatment conditions did not change the sensitivity of the parental cell line. Following treatment of the LoVo/DX cells with alpha-IFN plus 100 ng/ml Adriamycin for 1 h, 30% of the cells survived compared to 100% of untreated cells. This effect was not related to changes in cell cycle kinetics induced by alpha-IFN treatment and did not result from variations in the expression of P-glycoprotein at the cell surface, as assessed by flow cytometric analysis using monoclonal antibody MRK16. Adriamycin accumulation was increased by alpha-IFN as assessed by spectrofluorometric analysis. Thus, the data suggest that in LoVo/DX cells, alpha-IFN increased Adriamycin cytotoxicity through modulation of the multidrug resistance phenotype.
Cancer Res 1991 Sep 15
PMID:Reversal of adriamycin resistance by recombinant alpha-interferon in multidrug-resistant human colon carcinoma LoVo-doxorubicin cells. 189 80

Multidrug resistance (MDR) in cultured human cells is caused by the overexpression of the MDR-1 gene. This gene codes for P-glycoprotein, a proposed ATP-dependent drug efflux pump, which reduces the net intracellular accumulation of a large group of chemotherapeutic agents in resistant cells. We have measured the level of expression of the human MDR-1 gene in a series of patients with chronic lymphocytic leukaemia (CLL). Forty-eight patients included in the study were at different stages of disease and were either untreated or had been treated with alkylating agents or alkylating agents in combination with drugs of the MDR spectrum, and were tested over a period of 3 years. The level of MDR-1 expression was monitored by Northern blotting analysis using a specific cDNA hybridization probe and also after polymerase chain reaction (PCR) amplification of MDR-1 complementary DNA (cDNA). Four of 28 previously untreated patients showed intrinsically high levels of MDR-1 mRNA while 5/19 treated patients had elevated MDR-1 expression. Elevated MDR-1 expression in treated patients was unrelated to the type of chemotherapy and was independent of previous exposure to drugs of the MDR spectrum. Intrinsic MDR-1 gene expression in positive patients did not appear to influence their response to chemotherapy with non-MDR drugs such as alkylating agents.
Br J Haematol 1991 Sep
PMID:Analysis of multidrug resistance (MDR-1) gene expression in chronic lymphocytic leukaemia (CLL). 191 88

The overexpression of a cell-surface glycoprotein termed P-glycoprotein (P-gp) is frequently associated with multi-drug resistance (MDR) in cell lines in vitro. To evaluate the implications of P-gp expression in clinical drug resistance, the authors examined the expression of P-gp in leukemia cells from patients with acute myelogenous leukemia (AML) and those with acute lymphoblastic leukemia (ALL) at initial presentation and relapse, using immunoblotting with a monoclonal antibody against P-gp, C219. Nine of 17 patients with AML and four of 11 patients with ALL had P-gp-positive results at the initial presentation, and most P-gp-positive patients did not respond to chemotherapy. Four of seven patients at the relapsed stage and all three patients with preceding myelodysplastic syndrome had P-gp-positive results. The expression of P-gp and clinical refractoriness to chemotherapy were highly correlated. These data indicate that the expression of P-gp is closely related to clinical drug resistance in acute leukemia.
Cancer 1990 Sep 01
PMID:Expression of the multidrug transporter, P-glycoprotein, in acute leukemia cells and correlation to clinical drug resistance. 197 21

Two different mechanisms that contribute to multidrug resistance (MDR) were found in derivatives of the human squamous lung cancer cell line SW-1573. The parental cell line has a low amount of mdr1 P-glycoprotein mRNA. In three independent selections for doxorubicin resistance, MDR variants arose in which mdr1 P-glycoprotein mRNA and protein was not detectable. Selection on higher doxorubicin concentrations gave rise to variants containing high levels of mdr1 mRNA, due to transcriptional activation of the mdr1 gene. Upon continued selection for higher levels of doxorubicin resistance, the mdr1 gene became amplified, resulting in an additional increase in the level of mdr1 mRNA. The cross-resistance pattern of the sublines that lack mdr1 P-glycoprotein expression is different from that seen in the mdr1 overexpressing cells. Both types of MDR cell lines are resistant to doxorubicin, daunorubicin, etoposide, colchicine, gramicidin D, and vincristine. However, in the non-P-glycoprotein-mediated MDR cell lines, resistance levels are lower and a preferential resistance for etoposide is seen.
Cancer Res 1990 Sep 01
PMID:Non-P-glycoprotein mediated mechanism for multidrug resistance precedes P-glycoprotein expression during in vitro selection for doxorubicin resistance in a human lung cancer cell line. 197 23

We have characterized the normal human tissue distribution and tumor expression of the human multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) by immunohistochemical staining of frozen tissue sections of human normal and tumor tissues, using three mouse monoclonal antibodies (MAb) which recognize at least two different epitopes of Pgp. Pgp expression on normal human tissues was detected in specialized epithelial cells with secretory/excretory functions, trophoblasts in the placenta, and on endothelial cells of capillary blood vessels at blood-tissue barrier sites. There were significant differences in the staining patterns of these MAb. Mouse MAb HYB-241 and HYB-612 each recognize an extracellular epitope of Pgp, whereas mouse MAb C219 detects a carboxy terminal intracellular epitope and has recently been reported to crossreact with the MDR3 gene product. HYB-241 and HYB-612 strongly stain endothelial cells and trophoblasts, whereas C219 is weakly positive or unreactive on these cells. Likewise, C219 strongly stains the biliary pole of hepatocytes, skeletal and heart muscle fibers, whereas HYB-241 and HYB-612 are unreactive on these cells. Immunopathological studies were performed on a wide variety of human tumors. Pgp expression on human tumors was most commonly detected in colon. renal, and adrenal carcinomas; rarely in lung and gastric carcinomas and certain germ cell tumors; and was undetectable in breast and endometrial carcinomas tested. Few sarcomas and none of the melanomas, neuroblastomas, gliomas, and pheochromocytomas had detectable Pgp expression. Intensity and pattern of staining varied among different cases of a given tumor type; although homogeneous immunoreactivity was observed, heterogeneity of expression in a single histological section was more common. The finding of Pgp expression in a variety of normal tissues with diverse physiological functions suggests that the role of Pgp may not be limited to excretion of xenobiotics. Pgp expression in capillaries of the brain and testis may explain the failure of drugs such as vincristine and actinomycin-D to penetrate into these tissues, allowing them to remain as pharmacological sanctuaries for malignant cells. Although Pgp expression can now be detected in a variety of human tumors, further studies are needed to establish the possible significance of this finding.
J Histochem Cytochem 1990 Sep
PMID:Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. 197


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