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)

We have studied the patterns of P-glycoprotein expression before and after 3 cycles of induction chemotherapy (5-fluorouracil, adriamycin and cyclophosphamide) using immunohistochemically stained paraffin-embedded specimen of 28 patients with locally advanced breast cancer. The frequency of P-glycoprotein expression in untreated breast cancer turned out to be very low: only one out of 28 untreated, biopsy specimen at the time of diagnosis was positive. The frequency of P-glycoprotein expression was markedly increased from 9.1% before chemotherapy to 63.6% after induction chemotherapy (p = 0.006). After 3 cycles of induction chemotherapy, 25 patients had obtained clinical response to chemotherapy (4, CR; 21, PR). Eleven out of 25 tumors (44%) showing clinical response and all three tumors (100%) with minimal response have expressed P-glycoprotein. One out of 6 patients (16.7%) with microscopic residual tumor seen in mastectomy specimen expressed P-glycoprotein, whereas 13 of 22 patients (59.1%) with gross residual tumor showed the presence of P-glycoprotein (p = 0.08). The frequency of intrinsic P-glycoprotein expression in untreated breast cancer was quite low, but approximately half of the patients do acquire P-glycoprotein expression during the cycles of induction chemotherapy. Therefore, the results suggest that the immunohistochemical detection of P-glycoprotein on residual tumor cells after induction chemotherapy can predict acquired drug resistance in breast cancer.
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PMID:The value of immunohistochemical detection of P-glycoprotein in breast cancer before and after induction chemotherapy. 135 34

The effectiveness of ex vivo chemotherapy with drugs, such as vincristine, etoposide, and Adriamycin (doxorubicin, Adria Labs, Columbus, OH) for elimination of residual tumor cells from human bone marrow grafts could be undermined by the presence of multidrug-resistant tumor cells in the bone marrow. Therefore, to supplement chemoseparation, we investigated whether MRK-16, a monoclonal antibody (MoAb) to the surface moiety of multidrug resistance-associated P-glycoprotein antigen, can eliminate drug-resistant tumor cells in the presence of rabbit complement (RC). Two doxorubicin (DOX)-resistant human myeloma tumor cell line, 8226/DOX40 (resistant to 4 x 10(-7) mol/L DOX) and 8226/DOX6 (6 x 10(-8) mol/L DOX) with high and low amounts of cell surface P-glycoprotein, respectively, and the drug-sensitive parent cell line 8226/S were used as tumor models in this study. Using the limiting dilution assay, we have shown that three cycles of treatment with 25 micrograms/mL of MRK-16 MoAb and a 1:4 final dilution of RC eliminated 2.90 +/- 0.10 logs of 8226/DOX40 cells and 1.94 +/- 0.18 logs of 8226/DOX6 cells. One and two cycles of treatment were less effective, eliminating 0.47 +/- 0.40 and 1.94 +/- 0.36 logs of 8226/DOX40 and 0.12 +/- 0.20 and 1.63 +/- 0.58 logs of 8226/DOX6 cells, respectively. The 8226/S cell growth was unaffected by one to three cycles of treatment. The cell kill was not impaired when the antibody plus complement treatment was carried out on a mixture of 8226/DOX40 or 8226/DOX6 cells with a ninefold excess of irradiated bone marrow mononuclear cells (MNCs). The three cycles of treatment with antibody plus complement did not adversely affect granulocyte-macrophage colony-forming unit (GM-CFU) survival in hematologically normal marrows (92.5% to 104% survival) or in myeloma patient marrows (85% to 100%). These results show that it is possible to eliminate drug-resistant myeloma tumor cell lines from the admixed human bone marrow by treatment with MRK-16 MoAb plus RC. This method could prove to be effective for elimination of other drug-resistant tumor cell lines including those of leukemia and solid tumors, and will be further useful for supplementing chemopurging, and immunopurging of bone marrow with other antitumor cell antibodies.
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PMID:Elimination of drug-resistant myeloma tumor cell lines by monoclonal anti-P-glycoprotein antibody and rabbit complement. 257 83

Multidrug resistance, mediated by the overexpression of an energy-dependent transport protein, P-glycoprotein, has been one of the major targets of interest in solving the mechanisms of clinical drug resistance of malignant cells. To evaluate the correlation between P-glycoprotein overexpression and the response to chemotherapy, we analysed cytospin preparations of gradient-separated blood or bone marrow mononuclear cells from 79 patients with acute leukaemia by means of the P-glycoprotein-directed monoclonal antibody JSB-1 and immunocytochemistry using the alkaline phosphatase-antialkaline phosphatase technique. P-glycoprotein expression was detected in all disease phases of acute leukaemia. Thirteen out of 51 patients at diagnosis, 10/29 patients in relapse or during residual disease and 8/27 patients in remission overexpressed P-glycoprotein. Seven out of the 8 positive remission samples were collected between the cycles of consolidation treatment. Our results suggest that increased P-glycoprotein expression in samples collected between the cycles of consolidation treatment during remission may be induced in normal leukocytes by cytotoxic drug treatment, infections, or by some physiological mechanisms related to the disease. Patients older than 45 years of age were significantly more often P-glycoprotein-positive (11/25) at diagnosis than younger patients (2/26). P-glycoprotein expression at diagnosis was significantly correlated with a low remission rate after the first cycle of induction therapy. Of 34 P-glycoprotein-negative patients, 25 achieved remission after the first cycle as compared to 4/12 of the P-glycoprotein-positive patients. Our results indicate that the method used is specific and sensitive enough for the analysis of P-glycoprotein expression and that the expression at initial presentation is inversely correlated with the outcome of induction therapy.
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PMID:Clinical significance of P-glycoprotein expression in acute leukaemia as analysed by immunocytochemistry. 810 May 37

P-glycoprotein (P-gp) is a plasma membrane efflux transporter that maintains the intracellular concentration of chemotherapeutic agents at low levels. Since the clinical outcome of ovarian adenocarcinoma depends largely on its response to chemotherapy, an objective assessment of P-gp expression could serve as a prognostic indicator. Eighty-five patients were studied. Available tissue sections from the primary tumor (n = 75) and persistent or recurrent lesions (n = 19) were tested with anti-P-gp (JSB-1) monoclonal IgG. Multivariate survival analysis using Cox regression was performed controlling for fixed covariates (age, surgical stage, and presence of residual tumor) and included occurrence of postchemotherapy tumors and P-gp positivity in postchemotherapy neoplasms as time-dependent variables. P-gp was expressed in 49 prechemotherapy (65.3%) and 14 postchemotherapy (73.7%) tumors. After controlling for potentially confounding factors, patients with P-gp-positive postchemotherapy neoplasms were at three times greater risk of dying within 2 years than their counterparts with P-gp-negative tumors (hazard ratio = 3.1: 95% confidence interval = 1.2, 9.1; p < 0.05). Detection of P-gp-expressive subclones can serve as an independent poor prognostic indicator for patients with postchemotherapy tumors.
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PMID:P-glycoprotein as a prognostic indicator in pre- and postchemotherapy ovarian adenocarcinoma. 898 35

Intrinsic and/or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with ovarian carcinoma. The aim of the present study was to investigate the prognostic value of drug resistance-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), canalicular multispecific organic anion transporter (c-MOAT/MRP2), and lung resistance protein (LRP) in ovarian carcinoma. Expression of P-gp, MRP1, MRP2, and LRP was determined by immunohistochemistry of frozen tissue sections of 115 ovarian carcinoma patients and related to clinicopathological factors, response to chemotherapy, and progression-free survival. P-gp expression was observed in 20 of 115 (17%), MRP1 in 51 (44%), MRP2 in 19 (16%), and LRP in 85 (74%) tumors. Expression of MRP1 was related to MRP2 (P<0.0001) and P-gp (P<0.001) expression, whereas LRP expression was more frequently observed in patients with early stage (P<0.01), lower grade (P<0.05), and smaller residual tumor (P<0.05). Early stage (P<0.001), smaller residual tumor (P<0.001), and lower differentiation grade (P<0.05) were related to longer (progression-free) survival. P-gp, MRP1, MRP2, and LRP expression were neither related to response to first-line chemotherapy in 59 evaluable patients nor to progression-free survival in all patients. On multivariate analysis, only stage and residual tumor were independent prognostic factors for survival. In conclusion, in ovarian carcinoma, MRP1 expression is associated with MRP2 and P-gp expression, whereas LRP expression is associated with favorable clinicopathological characteristics. Assessment of P-gp, MRP1, MRP2, or LRP does not allow prediction of response to chemotherapy or survival in ovarian carcinoma.
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PMID:Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma. 1053 44

Pleiotropic resistance of tumor cells to treatment remains one of the major obstacles for successful cure of cancer patients. Tumor cells may acquire multidrug resistance (MDR) in the course of exposure to various compounds that are used in modern anticancer therapy, including cytotoxic drugs and differentiating agents. Therefore, the recurrence of the disease after the initial treatment may be associated with establishment of secondary MDR in the residual tumor. This phenotype is frequently mediated by P-glycoprotein, an ATP-dependent transmembrane pump capable of effluxing numerous compounds out of the cell. In humans, P-glycoprotein is encoded by the MDR1 gene. Rapid increase of the steady-state level of the MDR1 mRNA in response to stress stimuli is the mechanism of acquisition of P-glycoprotein-mediated MDR in cancer cells. Thus, up-regulation of the MDR1 gene is regarded as part of cellular stress response. This review shows that block of mechanisms that regulate the MDR1 overexpression can prevent the emergence of MDR in tumor cells that expressed null-to-low levels of MDR1 mRNA or P-glycoprotein prior to treatment. In particular, the MDR1 activation can be abrogated by targeting cytoplasmic pathways of signal transduction as well as by interfering with transcriptional up-regulation.
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PMID:Signal transduction pathways and transcriptional mechanisms as targets for prevention of emergence of multidrug resistance in human cancer cells. 1146 39

The aim of this study was to test the prognostic value of p-glycoprotein expression and the proliferative index of tumor cells on the clinical response to chemotherapy, on the brief disease-free interval (< 12 months) and on cause-specific survival in advanced ovarian carcinoma. We evaluated 83 ovarian carcinoma patients homogeneous for stage, type and grade histological. Brief disease-free interval and cause-specific survival rates (Kaplan-Meier method) were compared using the log rank test. Multivariate analysis (Cox proportional hazards models) was used to determine the independent effect of each variable on prognosis. In the univariate analysis, P-glycoprotein expression (P < 0.0005) and proliferative index (P = 0.0003 and P = 0.0006) were independent predictors of survival and brief disease-free interval; residual disease was associated with survival (P = 0.021). In multivariate analysis (Cox proportional hazards models), P-glycoprotein expression (P = 0.001 and P = < 0.0005) and proliferative index (P = 0.081 and P = 0.041) were independent predictors of brief disease-free interval and survival. P-glycoprotein expression (P < 0.0005) and proliferative index (P = 0.008) were associated with clinical response to chemotherapy.
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PMID:Prognostic value of P-glycoprotein and proliferative index in advanced low grade serous ovarian carcinomas. 1296 67

The aim of the study was to determine if biomarker expression could help discriminate between short-term and long-term survivors in women with advanced ovarian cancer. Fifty-one patients with stage III ovarian cancer were selected for the study, which included 28 short-term survivors (death from ovarian cancer within 18 months) and 23 long-term survivors (alive for more than 5 years). There was no difference between the two groups with respect to FIGO substage, age, World Health Organization score, and first-line platinum therapy. Classic clinical pathologic parameters were examined together with p53, Bcl-2, Ki-67, PDGFRalpha, P-glycoprotein, BRCA1, and DNA ploidy. Immunohistochemistry was used for scoring biomarker expression and image cytometry for DNA ploidy. All patients had primary debulking surgery followed by first-line platinum therapy. On multivariate analysis, the presence of ascites, debulking surgery and repeat laparotomy, clear-cell histology, elevated CA125, and high Ki-67 score were all found to be of prognostic importance. The long-term survivors were characterized by primary optimal cytoreduction surgery (<1 cm residual disease), attempt at maximal tumor debulking by experienced gynecological oncologic surgeons, and the absence of ascites. Normal CA125 level before platinum therapy and negative Ki-67 expression also predicted a more favorable prognosis.
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PMID:Prognostic factors in ovarian carcinoma stage III patients. Can biomarkers improve the prediction of short- and long-term survivors? 1634 77

Chemotherapy has proven to be effective in the management of high grade non-Hodgkin's lymphoma (NHL). However drug resistance remains a major clinical obstacle to effective disease control. One such well documented system involves multidrug resistance (MDR), characterized by the overexpression of a 170 kDa membrane protein termed P-glycoprotein (Pgp). Analysis of P-glycoprotein was done on lymph node biopsies obtained from 109 patients with high grade NHL. Patients were followed up for time periods ranging from 7 to 26 months after chemotherapy or until recurrent/residual disease was diagnosed. Analysis of Pgp in tissue samples was carried out by immunocytochemistry and Western blot. Of the 109 patients, 36 had either residual or recurrent disease. All these patients had a second lymph node biopsy done which was also analyzed for Pgp. P-glycoprotein was detected by immunocytochemistry in only 5 of the 73 patients who remained disease-free, while it was expressed in 26 of the 36 patients with residual/recurrent disease. All the 36 tissue samples of the latter group and 42 of the 73 biopsies of the disease-free group were re-analyzed by Western blot. Only one of the 42 samples from the disease-free group showed a positive Western blot reaction while 30 of the 36 samples from patients with recurrent/residual disease gave a positive reaction. Thirty-four of the 36 repeat biopsy samples from patients with recurrent/residual disease were positive for Pgp. Correlation analysis, thus showed significant relationship between prognosis and detection of Pgp by immunocytochemistry (r=0.85, p<0.001) and Western blot (r=0.90, p<0.001). Moreover, the odds ratio of a tumor positive for Pgp not responding to chemotherapy was 35.36 (CI 11.03, 113.37). Thus evaluation for Pgp may prove to be a useful prognostic marker for high grade NHL, and may also prove useful in designing or altering chemotherapy protocols in such patients.
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PMID:De novo expression of P-glycoprotein associated with poor prognosis in high grade non-Hodgkin's lymphoma. 2159 Feb 46

Although chemotherapy of tumours has scored successes, drug resistance remains the major cause of death of cancer patients. Initial treatment often leaves residual disease, from which the tumour regrows. Eventually, most tumours become resistant to all available chemotherapy. I call this pan-resistance to distinguish it from multi-drug resistance, usually describing resistance caused by upregulation of drug transporters, such as P-glycoprotein. In this review, I discuss mechanisms proposed to explain both residual disease and pan-resistance. Although plausible explanations are at hand for residual disease, pan-resistance is still a mystery. My conclusion is that it is time for a major effort to solve this mystery using the new genetically modified mouse tumour models that produce real tumours resembling cancer in human patients.
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PMID:Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? 2272 67


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