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)

To ezamine the clinical relevance of P-glycoprotein, encoded by the human multidrug resistance gene (MDR1), to multidrug resistance in lung cancer, we examined the expression of MDR1 in 107 non-small cell lung cancer (NSCLC) specimens and 20 corresponding specimens of normal lung tissues. We also evaluated the relationship between MDR1 expression and the histopathology and pathological staging of NSCLC. The tumors consisted of 60 adenocarcinomas, 38 squamous cell carcinomas, 8 large cell carcinomas, and 1 adenosquamous carcinoma. MDR1 expression was semi-quantified by use of the reverse transcriptase-polymerase chain reaction method. We subclassified the NSCLC into 3 grades according to the MDR1 expression level (-, +, ++). Sixty-one of the 107 tumor specimens (57%) and 18 of the normal lung tissue specimens (90%) expressed various levels of the MDR1 gene. Only one tumor specimen showed higher MDR1 expression than the corresponding normal lung tissue. The relationship between pathological stage and MDR1 expression levels was not significant. These results suggest that the level of MDR1 expression in lung cells is decreased as cells progress from the normal to the transformed state.
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PMID:Expression of the multidrug resistance gene (MDR1) in non-small cell lung cancer. 791 40

Cryptophycin is a cytotoxic dioxadiazacyclohexadecenetetrone isolated from cyanobacteria of the genus Nostoc. Incubation of L1210 leukemia cells with cryptophycin resulted in dose-dependent inhibition of cell proliferation in parallel with increases in the percentage of cells in mitosis (half-maximal effects at < 10 pM). Indirect immunofluorescence studies demonstrated that treatment of A-10 vascular smooth muscle cells with cryptophycin results in marked depletion of cellular microtubules and reorganization of vimentin intermediate filaments, similar to the effects of vinblastine. Cytochalasin B caused the depolymerization of microfilaments in these cells, while neither vinblastine nor cryptophycin affected this cytoskeletal component. Pretreatment of cells with taxol prevented microtubule depolymerization in response to either vinblastine or cryptophycin. While microtubule depolymerization in response to vinblastine was rapidly reversed by removal of the drug, cells treated with cryptophycin remained microtubule depleted for at least 24 h after removal of the compound. Combinational treatments with vinblastine and cryptophycin resulted in additive cytotoxicity. Ovarian carcinoma and breast carcinoma cells which are multiply drug resistant due to overexpression of P-glycoprotein are markedly less resistant to cryptophycin than they are to vinblastine, colchicine, and taxol. Therefore, cryptophycin is a new antimicrotubule compound which appears to be a poorer substrate for P-glycoprotein than are the Vinca alkaloids. This property may confer an advantage to cryptophycin in the chemotherapy of drug-resistant tumors.
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PMID:Cryptophycin: a new antimicrotubule agent active against drug-resistant cells. 791 8

Increased P-glycoprotein expression has been shown to be the molecular cause of multidrug resistance in tumor cell lines. Sensitive immunohistochemical and molecular biologic techniques have been developed to detect P-glycoprotein/mdr1 mRNA expression in clinical samples of tumors. We have reviewed the tools now available for assessment of P-glycoprotein expression in the clinic, the current evidence for a relevant role of the protein in mediation of resistance to chemotherapy, and one strategy used to overcome therapeutic failures due to multidrug resistance. It is now recognized that low levels of increased P-glycoprotein/mdr1 mRNA can occur at diagnosis and during the course of treatment in some cases of acute myelogenous leukemia, non-Hodgkin's lymphoma, multiple myeloma, breast carcinoma, rhabdomyosarcoma and undifferentiated sarcoma of children, neuroblastoma, and retinoblastoma, and these relatively low levels of mdr1 overexpression appear to be associated with poor prognosis. In contrast, it has not been established whether a multidrug resistance mechanism is the rate-limiting factor in response to chemotherapy in carcinomas that arise from tissues normally expressing increased P-glycoprotein. Clinical trials have been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy-treated malignancies. Preliminary results suggest that chemosensitizers can modulate the effects of increased P-glycoprotein in low-expressing tumors for which effective multiagent chemotherapy is available. Further research is needed for more potent chemosensitizers or combinations of agents that can be used more effectively. The successful circumvention of chemotherapy failure by chemosensitizers will ultimately establish the clinical relevance of the P-glycoprotein efflux mechanism.
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PMID:Multidrug resistance. Clinical opportunities in diagnosis and circumvention. 791 5

A major problem in cytostatic treatment of many tumours is the development of multidrug resistance (MDR4). This is most often accompanied by the overexpression of a membrane transport protein, P-glycoprotein, and its encoding mRNA. In order to reverse the resistant phenotype in cell cultures, we constructed a specific hammerhead ribozyme possessing catalytic activity that cleaves the 3'-end of the GUC sequence in codon 880 of the mdr1 mRNA. We demonstrated that the constructed ribozyme is able to cleave a reduced substrate mdr1 mRNA at the GUC position under physiological conditions in a cell-free system. A DNA sequence encoding the ribozyme gene was then incorporated into a mammalian expression vector (pH beta APr-1 neo) and transfected into the human pancreatic carcinoma cell line EPP85-181RDB, which is resistant to daunorubicin and expresses the MDR phenotype. The expressed ribozyme decreased the level of mdr1 mRNA expression, inhibited the formation of P-glycoprotein and reduced the cell's resistance to daunorubicin dramatically; this means that the resistant cells were 1,600-fold more resistant than the parental cell line (EPP85-181P), whereas those cell clones that showed ribozyme expression were only 5.3-fold more resistant than the parental cell line.
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PMID:Reversion of multidrug resistance in the P-glycoprotein-positive human pancreatic cell line (EPP85-181RDB) by introduction of a hammerhead ribozyme. 791 21

The role of estrogenic hormones on the induction of drug resistance was studied in cervical cancer cell lines, SiHa and Caski. After the cells were inoculated with estradiol (E2) or diethylstilbestrol (DES) in various dosages, the cell survival rates with adriamycin treatment were examined by MTT (3-[4,5-dimethyl-thiazole-2-yl]-2,5-diphenyl-tetrazolium-bromide) test and the intracellular accumulation of adriamycin was evaluated by flow cytometry. In the same condition, the expression of multidrug resistance gene-1 (mdr-1 gene) was detected either by Northern blot hybridization for mdr-1 mRNA or by immunoblot for P-glycoprotein 170. The data in this study indicated that estrogenic hormones had the capacity to induce drug resistance in cervical carcinoma cell lines. When cells were treated with estrogenic hormones and adriamycin simultaneously, the intracellular accumulation of adriamycin declined and corresponded with the drug resistance. Since the expression of the mdr-1 gene induced by E2 or DES results in drug resistance, it is suggested that the mdr-1 gene in SiHa cells may contain the estrogenic responsive element (ERE) in its regulatory region. However, the mechanism of drug resistance induced by estrogenic hormones in Caski cells is different from SiHa cells due to the absence of mdr-1 gene expression. Despite that, this experiment may provide a model to investigate the relationships between estrogenic hormones and drug resistance in other female genital cancers.
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PMID:The induction of multidrug resistance in human cervical carcinoma cell lines by estrogenic hormones. 791 38

P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been widely studied. Recent investigations have begun to focus on the relationship between Pgp detection in tumors and treatment outcome. In several types of tumors, detection of Pgp correlates with poor response to chemotherapy and shorter survival. P-glycoprotein over-expression often occurs upon relapse from chemotherapy but may also occur at the time of diagnosis. Studies of experimental rat liver carcinogenesis have shown that Pgp expression increases in late stages of carcinogenesis, suggesting that Pgp may be involved in tumor progression. While some of the Pgp isoforms are known to transport hydrophobic chemotherapeutic drugs out of tumor cells, the biologic effects of Pgp overexpression in tumor cells are not fully understood, because the spectrum of substrates for Pgp-mediated transport has not been determined. In the rat liver carcinoma model, strong expression of Pgp is associated with a highly vascular stroma, suggesting that Pgp in tumor cells may affect the connective tissue stroma. The regulation of Pgp appears to be complex, and little is known about how it is up-regulated during carcinogenesis. Further studies of the role of Pgp in malignancy may contribute to our understanding of molecular mechanisms which underlie tumor progression.
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PMID:P-glycoprotein, multidrug resistance and tumor progression. 792 52

The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant cell lines established from human larynx carcinoma HEp2 cells through repeated treatments with increased CDDP concentrations. CK2 cells obtained by continuous treatments were more resistant to CDDP than CA3 cells obtained by acute treatments. The examination of growth characteristics showed that both CDDP resistant cells had doubling times identical to that of the parental cells, but had lower plating efficiency. The possible involvement of glutathione (GSH), glutathione transferases (GST), metallothioneins, P-glycoprotein and drug accumulation in CDDP resistance was examined. Glutathione contents were elevated in both CDDP resistant lines. However, neither GSH nor GST were involved in CDDP resistance. This was demonstrated by simultaneous incubation of parental and CDDP resistant cells with CDDP and specific inhibitors of GSH and GST alpha and pi (buthionine sulfoximine and ethacrinic acid). Similarly, verapamil, an inhibitor of P-glycoprotein, did not influence the sensitivity of parental and resistant cells to CDDP. As compared to the parental cells, CK2 cells became resistant and CA3 cells became sensitive to cadmium, indicating increased level of metallothioneins in CK2 cells, and reduced level in CA3 cells. Measurements of platinum contents in parental and CDDP resistant cells after 1, 3 and 6 hours exposure to 70 mumol CDDP showed reduction in platinum accumulation after each exposure time in CK2 cells, and after 6 hours exposure in CA3 cells. This study identified decreased platinum accumulation as an important mechanism of CDDP resistance in human larynx carcinoma cells.
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PMID:Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): mechanisms involved in the resistance. 793 85

In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to cis-diamminedichloroplatinum(II) (CDDP) due to acute (CA3 cells), or continuous (CK2 cells) treatments with increased CDDP concentrations. CA3 line was 2.3-fold resistant, and CK2 line 3.7-fold resistant to CDDP as compared to the parental cells. In this study the sensitivity of CDDP resistant and parental cells to several antitumor drugs was examined using clonogenic survival assay. CK2 cells were 1.7-fold more resistant to vincristine than parental cells, while CA3 cells exhibited resistance to vincristine only at higher concentrations of this drug. Verapamil, an inhibitor of P-glycoprotein, was not able to reverse the resistance of CK2 cells to vincristine, indicating that this cross-resistance did not involve P-glycoprotein. As compared to the parental cells, CK2 cells were 2.1-fold resistant, and CA3 cells 1.7-fold resistant to mitomycin C. CK2 cells were 2-fold more resistant to 5-fluorouracil than the parental cells, while CA3 cells did not exhibit any change in the sensitivity to this drug. CA3 cells were 0.4-fold sensitive to epoxide and 0.53-fold sensitive to doxorubicin, while CK2 cells had the same sensitivity to these drugs as the parental cells. Our results showed that treatment schedule determines the response of CDDP resistant human larynx carcinoma cells to additional drugs, suggesting the complexity of the judicious choice of the drugs in the combined modality treatments of cancer.
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PMID:Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): cross-resistance patterns. 793 86

A bladder carcinoma cell line (J82) was selected for resistance to the new vinca alkaloid navelbine. The resistance factor of the resistant subline (J82-NVB) to navelbine was 17. P-glycoprotein was not detected in the membrane of J82-NVB cells. The lack of cross-resistance to multidrug-resistant (MDR) drugs such as doxorubicin, epipodophyllotoxins and colchicine, the absence of increase in navelbine efflux and the fact that a reduced accumulation of the drug cannot account for the resistance level confirmed that the phenotype of resistance of J82-NVB cells is not a classical MDR phenotype. Moreover, verapamil did not reverse the resistance of J82-NVB cells. The cells were cross-resistant to vinca alkaloids and taxoids which share the same target protein: tubulin. Analysis of microtubules using immunofluorescence showed that disassembly of the microtubular network occurred for the same concentration of navelbine in sensitive and resistant cells. However, after treatment with a concentration of navelbine inducing depolymerisation in both sensitive and resistant cells, reassembly of the microtubular network was observed only in resistant cells. This study suggests that the mechanism of resistance of J82-NVB cells involves recovery from the inhibition of microtubule dynamics induced by drug treatment.
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PMID:Characterisation of a navelbine-resistant bladder carcinoma cell line cross-resistant to taxoids. 798 Oct 63

Drug resistance in chemotherapy is a significant problem in the treatment of gastric carcinomas as well as other malignant tumors. Multidrug resistant cells frequently overexpress the 170 kDa P-glycoprotein (P-gp). Twenty-four fresh tumor specimens of gastric carcinoma were assessed by flow cytometric detection of P-gp using monoclonal antibody C219. Eight patients were P-gp positive. Differentiated gastric carcinomas contained significantly higher concentrations of P-gp positive. Incidence of P-gp positive case was high in advanced stage. Sixteen cases received in vitro chemosensitivity test assessed by thymidine incorporation assay (TIA). Seven of 9 multidrug resistant cases by TIA were P-gp positive, and all of 7 non-multidrug resistance were negative. Expression of P-gp and multidrug resistance were closely correlated (p < 0.01). Also, in 89 patients with operable gastric carcinoma, the relationship between multidrug resistance by TIA and their clinicopathologic features as well as their survival lengths were examined. Thirty-one of 89 specimens from gastric carcinoma patients were multidrug resistant by TIA. Patients with multidrug resistant group had a significantly poorer cumulative survival rate than non-multidrug resistant cases (p < 0.01). The multivariated analyses showed that multidrug resistance analyzed is useful indicator for prognosis (p < 0.1). We suggest that multidrug resistance cases or P-gp-positive cases of gastric carcinoma are highly malignant, and these determinations are clinically useful.
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PMID:[Clinical significance of P-glycoprotein expression and multidrug resistance assessed by in vitro thymidine incorporation assay in patients with gastric carcinoma]. 799 12


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