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 phenomenon that a tumour, resistant to a cytotoxic drug, is also resistant to a large number of other drugs used in cancer chemotherapy, is called multidrug resistance. A transmembrane protein, known as P-glycoprotein (P-gp), is involved in this resistance pattern. P-gp is able to pump large, lipophilic molecules out of the cell. 'Naturally occurring' drugs such as the anthracyclines and the Vinca alkaloids meet these criteria. To study the future clinical implications of multidrug resistance, we have gathered data in the literature on the presence of P-gp in haematological malignancies. At diagnosis 14-62% of all patients showed P-gp expression. Of previously treated patients 29-62% was positive for P-gp. A slight tendency to find a higher frequency of P-gp positivity in these previously treated patients was observed (so-called 'acquired resistance'). Early mutation and selection by the cytotoxic drug could account for the higher levels in treated patients. Chemotherapy itself could induce the expression of the P-gp pump. With the use of in vitro work various pharmacological agents have been found that can antagonize P-gp's function. Using these agents in clinical trials, some refractory patients showed a response to chemotherapy. We conclude that P-gp is probably just one of many causes of drug resistance in patients with haematological malignancies. Clinical results in some studies look promising, but many problems have still to be solved before common use.
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PMID:Multidrug resistance mediated by P-glycoprotein in haematological malignancies. 790 3

Anthracyclines and etoposide have been implicated in the multi-drug resistance phenotype. The mdr 1 gene encodes for the transmembrane protein P-glycoprotein. P-glycoprotein expression was measured in the fresh blast cells from 19 patients with acute myeloid leukemia using three monoclonal antibodies, C219, JSB-1 and MRK 16, and immunocytochemistry with the enzyme alkaline phosphatase as marker. Drug resistance can be identified in vitro using the predictive chemosensitivity test, the MTT (3-4,5-dimethylthiazol-2,5-diphenyl tetrazolium bromide) assay. In order to assess cell viability after drug exposure, this technique utilises the ability of cellular dehydrogenase enzymes to reduce the tetrazolium salt MTT to formazan. In vitro resistance to multi-drug resistance related cytotoxic agents was identified in the blast cells from these patients. This study showed no correlation between the results of the MTT assay and P-glycoprotein expression in this disease, suggesting either that more sensitive techniques are required to measure P-glycoprotein expression or that other drug resistance mechanisms may be involved.
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PMID:Comparison of P-glycoprotein expression with in vitro drug sensitivity in fresh blast cells from acute myeloid leukaemia patients. 852 96

P-glycoprotein (Pgp) is a transmembrane protein associated with multiple drug resistance. Pgp can be detected by several monoclonal antibodies or its activity inferred by measuring drug uptake. We compared two methods for quantitating Pgp in 32 patients with chronic lymphocytic leukaemia. The monoclonal antibody 4E3, which recognizes an external epitope of Pgp, was detected by flow cytometry. Intracellular daunorubicin (DNR) accumulation was measured by flow cytometry in the presence (treated) and absence (control) of cyclosporin, an agent known to inhibit Pgp. Correlation between the degree of positivity on the drug uptake assay and Pgp detected by monoclonal antibody 4E3 was poor (r = 0.06). No association with previous drug exposure or lymphocyte doubling time and Pgp positivity was found in this series of patients. Poor correlation between assays might reflect a lack of sensitivity of the DNR uptake assay. Drug accumulation may be influenced by other cellular efflux pumps unrelated to Pgp, making the DNR assay non-specific.
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PMID:Comparison of two methods to detect P-glycoprotein in patients with chronic lymphocytic leukaemia. 886 42

Multidrug resistance (MDR) in human cancer is often associated with over-expression of the mdr-1 gene, which encodes a 170-kDa transmembrane protein, termed P-glycoprotein (P-gp). We evaluated the immunoreactivity of P-gp in oral tissues at different stages of tumorigenesis in the Indian population by flow cytometry, using the MRK-16 monoclonal antibody, which recognizes an external epitope of P-gp. The expression of P-gp was studied in human oral normal tissues (12 cases), dysplastic lesions (13 cases), primary untreated squamous-cell carcinomas (12 cases) and recurrent tumors (18 cases). Quantitative flow-cytometric analysis of P-gp expression showed a significant increase in P-gp levels in untreated primary oral tumors (p < 0.01) and in dysplastic lesions (p < 0.05) as compared with normal oral tissues. A marked significant increase in P-gp expression was observed in recurrent oral carcinomas as compared with normal oral tissues (p < 0.001) and dysplastic lesions (p < 0.01). Among recurrent tumors, a significant increase in the level of P-gp was observed in T4-stage tumors as compared with T3-stage tumors (p < 0.01). We conclude that P-gp is differentially expressed during oral tumorigenesis, and may be an indicator of the biological behavior of oral malignancies.
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PMID:Differential expression of multidrug resistance gene product, P-glycoprotein, in normal, dysplastic and malignant oral mucosa in India. 903 81

Multidrug resistance (MDR) is an important problem in chemotherapy for neoplastic disease. In humans. MDR is mainly mediated by P-glycoprotein (P-gp) a product of the MDRI gene, which acts as a transmembrane protein pump and eliminates chemotherapeutic agents from the cells. Expression of P-gp was immunohistochemically studied by using two monoclonal antibodies, JSB-1 and C-219, on paraffin-embedded sections from 55 patients with soft-tissue sarcoma. The histological diagnosis of tumors was malignant fibrous histiocytoma in 24 cases, liposarcoma in 9, synovial sarcoma in 7, malignant neurogenic tumors in 6, leiomyosarcoma in 5, others in 4. The histological grade was determined on the basis of criteria previously proposed by us. Out of 55 cases, 34 (62%) were positive for P-gp expression. There was a significant difference in P-gp expression between high-grade (90%) and intermediate and low-grade tumors (46%) (P < 0.005). Tumors expressing P-gp had a less favorable prognosis than P-gp-negative tumors in the high- and intermediate-grade tumors. The current study demonstrated that the estimation of P-gp expression could be used to select appropriate therapeutic modalities.
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PMID:P-glycoprotein expression in soft-tissue sarcomas. 922 2

MDR1 P-glycoprotein (Pgp 170), a member of the adenosine triphosphate (ATP) binding cassette transporters, acts as an efflux pump for various hydrophobic agents, particularly for xenobiotics such as benzo(a)pyrene. It has also been shown to regulate cell-volume activated chloride channels. Pgp 170 could, therefore, be of particular importance in cellular mechanisms of defence in the airways and in the control of mucus layer composition. For these reasons, we evaluated the precise localization of Pgp 170 in human adult airways. Fresh non-neoplastic bronchial specimens were collected from 33 patients (26 smokers, four exsmokers and three nonsmokers) who underwent surgery for lung carcinoma. The presence of MDR1 messenger ribonucleic acid (mRNA) was demonstrated by reverse transcriptase chain reaction (RT-PCR) in bronchial epithelial cells collected by gentle scraping from either smokers, exsmokers or nonsmokers. Immunodetection of Pgp 170 using a panel of monoclonal antibodies (MRK16, JSB1, C219, C494) was performed either on cryostat or paraffin-embedded sections of histologically normal bronchial tissue. Pgp 170 was constantly detected with intense labelling at the apical surface of ciliated epithelial cells from the surface epithelium or ciliated collecting ducts, and on apical and lateral surfaces of serous cells from bronchial glands. No staining of mucus-secreting cells was observed. Pgp 170 was also demonstrated at the luminal surface of endothelial cells of bronchial capillaries. In conclusion, the expression of MDR1 P-glycoprotein in bronchial structures, particularly at the epithelial apical surface, suggests important roles for this transmembrane protein in human airways.
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PMID:MDR1-Pgp 170 expression in human bronchus. 927 28

1. P-glycoprotein (P-gp) is a transmembrane protein involved in ATP-dependent efflux of various structurally unrelated anticancer drugs. Its overexpression in cancer cells decreases intracellular drug concentrations and, thus, confers a multidrug resistance phenotype. 2. P-gp is encoded by MDR genes, which constitute a small gene family comprising two genes in humans and three genes in rodents. Only the MDR1 gene in humans and mdr1 and mdr3 genes in rodents have been demonstrated to be involved in drug resistance. 3. P-gp encoded by the human MDR1 gene is a phosphorylated and glycosylated protein 1289 amino acids long, and consists of 2 halves that share a high degree of similarity. 4. A wide variety of cancers have been shown to express P-gp, including solid tumors and hematological malignancies. This P-gp positivity can be evidenced at the time of diagnosis prior to chemotherapy or at relapse after treatment, and has been correlated with treatment failure and poor prognosis in several types of cancer. In addition, P-gp is also expressed by some normal tissues, such as liver and kidney. 5. P-gp expression is regulated by various factors, including xenobiotics and hormones. 6. P-gp-mediated multidrug resistance can be reversed by various unrelated compounds called chemosensitizers or reversing agents. These drugs act through inhibition of P-gp function and have entered clinical trials.
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PMID:The P-glycoprotein multidrug transporter. 930 97

P-glycoprotein (Pgp) is an inducible transmembrane protein that functions as an ATP-dependent efflux pump. Pgp is normally expressed in two types of cells: specialized epithelial cells with secretory/excretory functions (e.g., proximal renal tubules) and specialized endothelial cells (e.g., the capillary endothelial cells of the blood-brain barrier). In normal tissues, Pgp could exert a cytoprotective effect by facilitating excretion of drugs. It follows that inhibition of Pgp would alter the pharmacokinetics of drugs, like doxorubicin, in cells that express Pgp. The purpose of this study was to determine whether or not inhibition of Pgp by cyclosporin A (CsA) facilitated the transport of certain drugs across the blood tissue barriers of the brain and testes (barriers tissues expressing Pgp). 120 retired male breeder CD Fisher rats were randomly assigned to groups of 4 rats each. They were given either CsA, CsA vehicle, or saline followed by doxorubicin (Dox), cisplatin (CDDP), Evan's blue (EB), sodium fluorescein (NaF), or horseradish peroxidase (HRP). There was a CsA dose dependent increase in the tissue concentration of doxorubicin in brain and testes, but platinum (Pt) concentrations, derived from CDDP, were unaffected. Unlike CDDP, Dox, can be effluxed by Pgp. These increases in Dox concentrations were not due to altered vascular permeability as a result of CsA treatment as determined by lack of EB. NaF, or HRP in brain parenchyma. Modulation of Pgp function may prove to be useful for improving chemotherapy efficacy for patients with malignancies affecting tissues with blood-tissue barriers.
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PMID:Modulation of doxorubicin concentration by cyclosporin A in brain and testicular barrier tissues expressing P-glycoprotein in rats. 952 37

The polyspecific drug transporter OCT1 is a plasma transmembrane protein involved in the uptake of cationic drugs into hepatocytes. In order to determine whether hepatic OCT1 levels, like those of the other cationic drug transporter P-glycoprotein, may be altered during hepatocarcinogenesis, we have investigated OCT1 expression and activity in rat liver carcinoma cells. Similar levels of OCT1 mRNAs were evident in both normal liver and diethylnitrosamine-induced hepatocarcinomas by Northern blot analysis. In contrast, five hepatoma cell lines (Fao, Faza, H5, HTC and RHC1) showed either a decrease or an absence of OCT1 expression compared to normal hepatocytes; these hepatoma cells also displayed lower intracellular accumulation of tetraethylammonium (TEA), a well-known substrate for OCT1. However, among the hepatoma cell lines, the well-differentiated Fao cell line was found to retain substantial levels of OCT1 expression and of intracellular TEA uptake. Therefore, these data provide the first evidence that OCT1 expression is well-preserved in chemically-induced rat malignant neoplastic liver lesions, whereas it is either decreased or undetectable in hepatoma cell lines, which may be related to the loss of various liver functions usually occurring in these cell lines.
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PMID:Differential expression of the polyspecific drug transporter OCT1 in rat hepatocarcinoma cells. 958 71

We reviewed mechanisms of multidrug resistance (MDR) phenotype in tumor cells and evaluated analytical methods for detection of clinical MDR. A well-recognized mechanism of MDR phenotype is the induction and increased expression of P-glycoprotein (P-gp) which is a 170 kDa cellular transmembrane protein encoded by a multidrug-resistance 1 gene (MDR1) and works as a drug efflux pump. Cellular MDR phenotype through P-gp/MDR1 can be detectable at protein level by: (1) using immunohistochemical method, flow cytometric assay and Western blot analysis with monoclonal antibodies against human P-gp, and (2) measuring Rhodamine 123 dye-efflux as a functional assay of P-gp. Molecular knowledge and recent technical progress enable to determine MDR1 gene expression by RT-PCR-based analytical methods as well as conventional quantification methods of gene expression such as Northern blot analysis. In the evaluation of P-gp/MDR1 expression in clinical samples, in which amount of materials was limited, utilization of simple and sensitive methods like competitive RT-PCR assay might be efficacious for its quantitative detection in clinical laboratories. Evidences which showed the positive correlation between the expression of P-gp/MDR1 and clinical resistance or refractoriness of tumor cells to anticancer drugs involved in MDR have been accumulated and support the clinical importance of its detection to circumvent resistance with alternate use of non-MDR drugs.
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PMID:[Mechanisms of multidrug resistance in tumor cells and analytical methods for its detection]. 976 Aug 26


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