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)

Modulation of the expression of P-glycoprotein, a plasma membrane protein associated with multidrug resistance, was examined in drug-sensitive and drug-resistant tumor cells treated with leukoregulin, a M(r) 50,000 cytokine from human lymphocytes that rapidly permeabilizes the plasma membrane of many tumor cells facilitating the uptake of doxorubicin and other tumor-inhibitory antibiotics. P-glycoprotein expression was measured flow cytometrically by the binding of C219 or MRK16 monoclonal antibody to multidrug-sensitive human K562 erythroleukemia and 8226/S myeloma cells, compared to multidrug-resistant 8226/DOX40 myeloma cells. Cells were treated for up to 2 h with up to 80 units of leukoregulin/ml or one of a variety of unrelated cytokines including interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, colony-stimulating factor, macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, gamma-interferon, alpha-interferon, epidermal growth factor, platelet-derived growth factor AA, platelet-derived growth factor BB, insulin-like growth factor I, insulin-like growth factor II, fibroblast growth factor, or transforming growth factor beta. Leukoregulin caused a concentration-dependent decrease in P-glycoprotein expression; however, P-glycoprotein expression was unaffected by the other cytokines (< 12% decrease in expression). Leukoregulin-induced membrane permeabilization, determined flow cytometrically by intracellular fluorescein efflux, and decreased P-glycoprotein expression occurred simultaneously within 15 min in drug-sensitive and -resistant cells. Enhanced doxorubicin uptake, measured flow cytometrically by doxorubicin influx, was also present within 15 min. Leukoregulin enhancement of doxorubicin uptake and increased membrane permeability varied directly with the decrease in P-glycoprotein expression. Leukoregulin in combination with doxorubicin enhanced the inhibition of cell proliferation in 8226/DOX40 multidrug-resistant cells over expressing P-glycoprotein. In contrast, combined treatment of HL-60/MX2 multidrug-resistant human promyelocytic leukemia cells that do not overexpress P-glycoprotein in association with their multidrug resistance resulted in no greater growth inhibition than observed with HL-60/MX2 cells treated with doxorubicin alone. This is the first demonstration that a naturally occurring macromolecule with anticancer activities can modulate the expression of P-glycoprotein concomitant with enhanced drug uptake and inhibition of cell proliferation.
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PMID:Decreased P-glycoprotein expression in multidrug-sensitive and -resistant human myeloma cells induced by the cytokine leukoregulin. 135 22

P-glycoproteins encoded by members of the mdr gene family function as membrane-situated transport proteins, isoforms of which are involved in conferring a form of multidrug resistance by participating in secretion of various xenobiotics. In primary rat hepatocytes maintained in serum-free culture, accumulation of immunodetectable P-glycoprotein and mdr1b mRNA occurred in a time-dependent manner and was accompanied by a substantial decrease in retention of the mdr1 substrate rhodamine 123. However, incubation of cells with epidermal growth factor (EGF) or with insulin-like growth factor I (IGF-I) markedly enhanced time-dependent accumulation of P-glycoprotein and mdr1b mRNA. Furthermore, EGF-treated cells exhibited decreased intracellular rhodamine 123 retention, an effect partially inhibited by the chemosensitizer verapamil. These data suggest that an increase in (a) functional transporter(s) eliciting transport of mdr1 substrates occurs under EGF.
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PMID:Modulation of P-glycoprotein and mdr1b mRNA expression by growth factors in primary rat hepatocyte culture. 757 88

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 25% of all bronchogenic carcinoma and is associated with the poorest 5-year survival of all histologic types. SCLC differs in its etiologic, pathologic, biologic, and clinical features from non-SCLC, and these differences have translated to distinct approaches to its prevention and treatment. Compared with other histologic types of lung cancer, exposures to tobacco smoke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification of SCLC has been revised to include three categories: (1) small cell carcinoma, (2) mixed small cell/large cell, and (3) combined small cell carcinoma. Ultrastructurally, SCLC displays a number of neuroendocrine features in common with pulmonary neuroendocrine cells, including dense core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface antigens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor suppressor genes in SCLC have been described. Dominant proto-oncogenes that have been found to be amplified or overexpressed in SCLC include the myc family, c-myb, c-kit, c-jun, and c-src. Altered expression of two tumor suppressor genes in SCLC, p53 and the retinoblastoma gene product, has been demonstrated. Cytogenetic and molecular evidence for chromosomal loss of 3p, 5q, 9p, 11p, 13q, and 17p in SCLC has intensified the search for other tumor suppressor genes with potential import in this malignancy. Bombesin/gastrin-releasing peptide, insulin-like growth factor I, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investigation. Several mechanisms of drug resistance in SCLC have been described, including gene amplification, the recently described overexpression of multi-drug resistance-related protein (MRP), and the expression of P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive disease are equivalent to the TNM stages I through III and stage IV, respectively. Therapeutically, recent strategies have attained small improvements in survival but significant reductions in the toxicities of chemotherapeutic regimens. Presently, the overall 5-year survival for SCLC is 5% to 10%, with limited disease associated with a significantly higher survival rate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Small cell lung cancer: etiology, biology, clinical features, staging, and treatment. 839 98

Expression of HER2 was evaluated by immunohistochemical techniques in 84 osteosarcoma (OS) and 113 Ewing's sarcoma (ES) paraffin-embedded tumour biopsies. HER2 gene status was also assessed in a panel of cell lines as well as in vitro efficacy of trastuzumab (a humanised antibody directed against HER2) as single agent or in combination with the insulin-like growth factor I receptor (IGF-IR) IR3 antibody. Overexpression of HER2 was present in 32% of OS and 16% of ES and was significantly associated with the increased expression of P-glycoprotein, a surface molecule responsible for multidrug resistance. Event-free survival analyses revealed a prognostic value for HER2 and/or P-glycoprotein expression in OS, but not in ES. However, despite its prognostic relevance, no therapeutic effectiveness was observed pre-clinically for trastuzumab-driven therapy, in both OS or ES cell lines, unless the antibody was associated with anti-IGF-IR targeting strategies. Therefore, the therapeutic potential of trastuzumab in these neoplasms may be better exploited in combined treatments with anti-IGF-IR approaches.
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PMID:Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing's sarcoma. 1591 90