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)

Expression of P-glycoprotein (Pgp), the product of the multidrug resistance (MDR1) gene, detected by flow cytometric analysis of the binding of antibody 4E3.16, was found on significantly fewer leukemic cells in 35 adult patients with de novo acute promyelocytic leukemia (APL) (mean 14.8%, median 7%) than in 184 patients with non-APL acute myeloid leukemia (AML) at diagnosis (mean 28.3%, median 18%) (p = 0.0038). APL was diagnosed based on morphology, the detection of t(15;17) and of the chimeric fusion transcript PML/RAR alpha by PCR. To further substantiate low MDR1 expression in APL, we studied cells from 11 APL patients at the molecular and functional level in comparison to 48 non-APL cases. The diagnosis of APL was associated with the absence of Pgp function by the rhodamine efflux assay (p = 0.0001). Furthermore, MDR1-specific transcript levels, determined by quantitative PCR with two distinct sets of primers, were significantly lower in mononuclear cells from the APL than the other AML cases (p = 0.013). The frequency of leukemic cells positive for CD34, an antigen presumably associated with Pgp expression in AML, was significantly lower in APL than other AMLs (p = 0.0001). In contrast to non-APL leukemias, those few cases of CD34 strongly positive APL neither expressed Pgp nor contained significant MDR1 transcript levels. Low expression of Pgp by APL cells may provide the biologic basis for the high sensitivity of this leukemia subtype to chemotherapeutic agents in vivo.
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PMID:Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses. 751 29

In order to further define the role of the MDR1 gene in acute myeloid leukemia (AML), we determined the association between the presence of P-glycoprotein on leukemic cells and the efficacy of therapy in patients with AML. Immunocytochemistry with monoclonal antibody C219 was performed to demonstrate the presence of P-glycoprotein. Positive staining ranged from 0 to 60% of the leukemic cells. For further analysis, patients were assigned into groups with 0-5% staining cells (group 1, n = 33) and with > 5% staining cells (group 2, n = 19). The complete remission rate of induction chemotherapy was 76% for group 1 but only 32% for group 2 (p = 0.002). The median duration of overall survival was 19 months for patients in group 1 as compared to 3 months for patients in group 2 (p = 0.007). The data indicate that P-glycoprotein expression is associated with an unfavorable prognosis in patients with AML.
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PMID:P-glycoprotein expression as unfavorable prognostic factor in acute myeloid leukemia. 751 30

Tumor cell resistance to cytotoxic drugs is considered one of the major obstacles to successful chemotherapy. Multidrug resistance (MDR) describes the simultaneous expression of cellular resistance to a wide range of structurally and functionally unrelated drugs. The development of the multidrug resistance phenotype is accompanied by multiple morphological and biochemical changes: (a) increased glutathione levels in the cytoplasm, (b) modified levels of enzymes in the nucleus, particularly topoisomerase II, (c) increased DNA repair capacity and (d) overexpression of the (human) MDR1 gene encoding a transmembrane efflux pump (P-glycoprotein, gp-170), which leads to decreased intracellular accumulation and therefore to resistance to a variety of cytotoxic drugs. In this report we describe a competitive polymerase chain reaction (PCR) assay for the absolute quantification of MDR1 mRNA. This assay uses a transcript generated in vitro as an internal standard which is later coamplified together with the MDR1 cDNA. Both cDNAs exhibit the same MDR1 primer sites but differ in the length of the amplicon. For a second round of amplification we applied nested MDR1 primers and were successful in improving the sensitivity of this competitive PCR system. This test for characterizing the MDR1 expression offers high sensitivity and specificity and is therefore of great clinical relevance. It should be useful in improving monitoring and design of chemotherapy.
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PMID:Competitive nested polymerase chain reaction for quantification of human MDR1 gene expression. 751 88

The physiologic expression of the human multidrug resistance MDR1 gene product P-glycoprotein is controlled in a tissue- and cell-specific manner, but the regulatory mechanisms have not been characterized in great detail. Studies by Kohno et al. [(1990) J Biol Chem 265:19690-19696] suggested that a tissue-specific enhancer element located approximately 10 kb upstream from the major MDR1 transcription start site may act to increase the levels of transcription in cultured adrenal and kidney cells. Using this putative "MDR enhancer" as a probe, we isolated a 14 kb DNA fragment from a genomic DNA library prepared from human fetal liver. The restriction map and partial nucleotide sequence of this DNA fragment were consistent with the previously described data obtained for a similar piece of genomic DNA derived from human placenta by Kohno et al. (ibid.). Pulsed-field gel electrophoresis of large genomic DNA fragments, however, showed that the DNA sequences, including the putative "MDR enhancer," were not linked to the MDR1 gene. Fluorescence in situ hybridization analysis revealed that this enhancer-like element is located on chromosome 20 at band q13.1 and is, therefore, distinct from the MDR locus on chromosome 7, band q21.1. Thus, this putative regulatory element does not modulate the tissue specificity of expression of the MDR1 gene in vivo, but may play a role in the regulation of expression of another, so far unknown gene.
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PMID:Putative "MDR enhancer" is located on human chromosome 20 and not linked to the MDR1 gene on chromosome 7. 752 41

P-glycoprotein (PGP), responsible for multidrug resistance (MDR) in cancer cells, is normally expressed in kidney proximal tubules and mesangium. PGP expression and function were studied in human mesangial cell cultures. MDR1 gene expression was demonstrated by reverse transcription-polymerase chain reaction. PGP expression was determined using MRK16 monoclonal antibody and its function was assessed by the efflux of rhodamine-123 (R123). R123 efflux had a half time of 25 +/- 5 s. Efflux was inhibited by cyclosporin A (10 microM), verapamil (10 microM), and vinblastine (100 microM) with half times of 380, 535, and 312 s, respectively. Incubation with MDR1-antisense oligonucleotide decreased R123 efflux (half time = 304 s). Verapamil, cyclosporin A, and PSC-833 augmented the cytotoxicity of Adriamycin by reducing the 50% maximal growth-inhibitory dose from 730 nM to 130, 110, and 90 nM, respectively. We conclude that human mesangial cells express MDR1 and demonstrate xenobiotic transport inhibitable by several known PGP substrates. Concomitant exposure of mesangial cells to PGP-transported drugs causes intracellular accumulation of toxic PGP substrates and ultimately damages the mesangial cells.
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PMID:Expression and function of P-glycoprotein in human mesangial cells. 752 96

To analyze the mechanism of drug transport, mechanism of inhibitors, and physiological substrates of human P-glycoprotein, we established a transepithelial transport system by introducing MDR1 cDNA into LLC-PK1, a pig kidney epithelial cell line. P-glycoprotein functions as a steroid transporter as well as a drug transporter as physiological functions. P-glycoprotein also transports MDR modulators such as cyclosporin A, FK506, and calcium channel blockers.
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PMID:Human P-glycoprotein as a multi-drug transporter analyzed by using transepithelial transport system. 753 9

The MDR1 gene, a multidrug resistance gene, codes for P-glycoprotein which pumps hydrophobic drugs out of the cells. Since cyclosporins also bind to P-glycoprotein and might be pumped by this transmembrane protein, we determined the expression of the MDR1 gene in the lymphocytes of 32 patients with renal transplants. MDR1 RNA expression of lymphocytes was measured by slot blot analysis and compared to the expression of drug-sensitive KB-3-1 cells and multidrug-resistant KB-8-5 cells. MDR1 RNA expression was detected in the lymphocytes of 9 (28%) patients, whereas no expression was seen in the remaining 23 patients. No association between MDR1 RNA expression and transplant function or hematological parameters was observed. However, none of the 6 patients who had transplants for more than 40 months expressed the MDR1 gene in their lymphocytes. In conclusion, expression of the MDR1 gene does occur in lymphocytes of patients with renal transplants and might reduce the immunosuppressive efficacy of cyclosporins through enhanced efflux of cyclosporins.
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PMID:MDR1 gene expression in lymphocytes of patients with renal transplants. 753 32

The efficacy of verapamil and cyclosporine A as modulators of P-glycoprotein, the multidrug resistance (MDR1) gene product, was studied in leukemic blast cells from 56 patients with de novo acute myeloid leukemia (AML) in vitro. Rhodamine123 dye-efflux was measured flow cytometrically as a cellular parameter reflecting P-glycoprotein activity. While dye-efflux was measurable in 3/4 of the cases, the capacity of the P-glycoprotein inhibitors varied substantially among patients. In 23 patients, P-glycoprotein function was completely inhibited by the resistance modulators, whereas in 17 patients neither verapamil nor cyclosporine had any reverting effect on dye-efflux at concentrations even 10-times higher than achievable in vivo. Cells with a drug-sensitive rhodamine123-pump effluxed more efficiently (p = 0.0016) and contained significantly higher levels of MDR1 specific RNA transcripts (p = 0.0002), as determined by quantitative PCR, than cells exhibiting an efflux process that could not be inhibited. However, flow cytometric evaluation of the staining of gated blast cells with the anti-P-glycoprotein antibody, 4E3.16, revealed no difference in P-glycoprotein expression between modulator-sensitive and -insensitive cases (p = 0.86), indicating disproportionate translation of MDR1 mRNA. In leukemic cell populations with increased P-glycoprotein function that could be inhibited, significantly more blasts expressed the progenitor cell antigen, CD34 (median 83%), than was the case in leukemias with P-glycoprotein activity that could not be inhibited (median 7%) (p = 0.0001). The present study demonstrates that a substantial fraction of AML patients constitutively display a drug-efflux mechanism suggestive of P-glycoprotein activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of multidrug resistance in de novo adult acute myeloid leukemia: variable efficacy of reverting agents in vitro. Eastern Cooperative Oncology Group. 754 Sep 3

Cancer patients treated with one anticancer agent often develop resistance to a broad spectrum of chemotherapeutic agents. This type of multiple drug resistance (MDR) is often accompanied by a decrease in drug accumulation and an increase in expression of a 170,000-Da plasma membrane glycoprotein (P-170) that can effectively pump various anticancer agents out of cytoplasm. A panel of 12 IgG1, IgG2a, or IgG2b monoclonal antibodies was generated against the extracellular portion of P-glycoprotein by immunizing mice with a human MDR1 gene-transfected BA3T3 fibroblast line. We have characterized two of the anti-P-glycoprotein monoclonal antibodies, 15D3 and 17F9, in some detail. Both antibodies immunoprecipitate a 170- to 180-kDa protein from MDR cells, but do not block binding of the known anti-P-glycoprotein antibody MRK16, suggesting that 15D3 and 17F9 bind to a different epitope on the extracellular domain of P-glycoprotein than MRK16. Scatchard analysis revealed that 15D3 and 17F9 had association constants of 1.3 and 1.1 x 10(8) M-1, respectively. 15D3 and 17F9 had little effect on MDR cell growth except for a minor inhibition of KB-V1 cells when the cells were incubated in the presence of vinblastine. Neither antibody inhibited the efflux of P-glycoprotein substrates from MDR cells. Because of their strong binding activity, these antibodies may be useful for diagnostic detection of MDR in patients undergoing chemotherapy or as targeting components of immunotherapeutic agents.
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PMID:High-affinity monoclonal antibodies against P-glycoprotein. 754 35

Multidrug resistance (MDR) in mammalian cells and tumors is associated with overexpression of an approximately 170 kDa integral membrane efflux transporter, the MDR1 P-glycoprotein. Hexakis (2-methoxyisobutyl isonitrile)technetium(I) (Tc-SESTAMIBI), a gamma-emitting lipophilic cationic metallopharmaceutical, has recently been shown to be a P-glycoprotein transport substrate. Exploiting the negligible lipid membrane adsorption properties of this organometallic substrate, we studied the transport kinetics, pharmacology, drug binding, and modulation of P-glycoprotein in cell preparations derived from a variety of species and selection strategies, including SW-1573, V79, Alex, and CHO drug-sensitive cells and in 77A, LZ-8, and Alex/A.5 MDR cells. Rapid cell accumulation (t1/2 approximately 6 min) of the agent to a steady state was observed which was inversely proportional to immunodetectable levels of P-glycoprotein. Many MDR cytotoxic agents inhibited P-glycoprotein-mediated Tc-SESTAMIBI efflux, thereby enhancing organometallic cation accumulation. Median effective concentrations (EC50; microM) were as follows: vinblastine, 13; daunomycin, 55; idarubicin, 65; actinomycin D, 235; colchicine, minimal inhibition; adriamycin, no effect. P-glycoprotein modulators generally demonstrated significantly greater potency (EC50; microM): SDZ PSC 833, 0.08; cyclosporin A, 1.3; verapamil, 4.1; quinidine, 6.4; prazosin, > 300. Modulator-induced enhancement up to 100-fold was observed with Hill coefficients approximately 1, consistent with simple Michaelis-Menten kinetics. Vanadate was an efficacious transport inhibitor, while agents usually not included in the MDR phenotype were without effect. Scatchard analysis showed quinidine to be a noncompetitive inhibitor of P-glycoprotein-mediated Tc-SESTAMIBI transport, indicating allosteric effector sites on P-glycoprotein. The lipid bilayer adsorbing agents tetraphenyl borate and phloretin induced large increases in final Tc-SESTAMIBI accumulation, showing maximal accumulations 2-fold greater than classic MDR modulators and Hill coefficients >> 2. In V79 and 77A cells, modulators of PKC activity altered Tc-SESTAMIBI accumulation, while there was no indication of modulation of P-glycoprotein-mediated Tc-SESTAMIBI transport by hypotonic buffer, extracellular ATP, Cl-, or K+ (membrane potential). While recognized and avidly transported by the P-glycoprotein at buffer concentrations as low as 7 pM, Tc-SESTAMIBI at up to 100 microM only minimally modulated the cytotoxic action of colchicine, doxorubicin, or vinblastine in MDR cells. In conclusion, transport analysis with Tc-SESTAMIBI is a sensitive assay for detecting functional expression of low levels of P-glycoprotein and for the quantitative characterization of transporter modulation and regulation. The biochemical data favor a high Km, high capacity allosterically modulated translocation mechanism for P-glycoprotein-mediated transport of this organometallic cation.
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PMID:Characterization of multidrug resistance P-glycoprotein transport function with an organotechnetium cation. 754 62


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