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)

A human diffuse large cell lymphoma line (WSU-DLCL) expressing multidrug resistance (MDR) was established from a patient with primary chemotherapy-resistant disease. This cell line has the same phenotypic features as malignant cells from the patient. The established cell line has features of a mature B-cell neoplasm with no evidence for commitment to other lineages. WSU-DLCL grows in suspension forming relatively large clumps of cells with a doubling time of 20 hours. By light microscopic examination, the cells are very large with primitive lymphoid features, have a large amount of cytoplasm containing numerous vacuoles and an irregular outline. Immunophenotypic characterization by monoclonal antibodies and flow cytometric analysis showed a monoclonal IgM kappa B-cell phenotype with high expression of the multidrug-resistant P-glycoprotein compared with either normal peripheral blood lymphocytes or cells of the REH cell line. The cells were negative for T-cell and myeloid/monocyte antigens as well as Epstein-Barr virus nuclear antigen (EBNA). In addition, the cell line expressed high levels of MDR RNA. DNA histogram generated by flow cytometry indicated a DNA index of 1.83. Cytogenetic analysis confirmed hypertriploidy and showed complex chromosomal abnormalities including 14q+. This cell line should be a valuable tool to study the role of the MDR gene in the primary resistance of lymphomas to chemotherapy and to facilitate therapeutic investigations.
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PMID:A human B-cell lymphoma line with a de novo multidrug resistance phenotype. 154 Aug 84

The virus-associated T cell leukaemias/lymphomas are characterized by a poor prognosis primarily because of the rapid emergence of drug resistance which may lead to failure of subsequent chemotherapy. We report here a case of Epstein-Barr virus-associated T cell lymphoma which relapsed soon after chemotherapy and radiotherapy. The neoplastic cells of the relapsed tumour expressed high levels of multi-drug resistance gene (mdr1)-related P-glycoprotein and glutathione-S-transferase-pi, both of which were absent in the pre-chemotherapy tumour tissues. Empirical treatment with oral 13-cis-retinoic acid (RA) was then given with subsequent complete disappearance of the tumour. The therapeutic effect of RA appears to act through an apoptotic process. In accordance with our previous report of a successful salvage of a refractory Ki-1 large cell lymphoma. RA appears to be a potentially useful drug for some specific type T-cell lymphomas.
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PMID:Retinoic acid-induced apoptosis and regression of a refractory Epstein-Barr virus-containing T cell lymphoma expressing multidrug-resistance phenotypes. 791 55

Chronic granulomatous disease (CGD) is a group of disorders characterized by the failure of phagocytes to produce superoxide. One-third of the cases of CGD in the USA and Europe results from defects in the gene encoding p47phox, a cytoplasmic component of NADPH oxidase for superoxide generation. In this study, we constructed the bicistronic retrovirus vector Ha-MDR-IRES-p47, which carries cDNAs for a human multi-drug-resistance gene (MDR1) and p47phox. The amphotropic retroviral producer cells were generated, and the supernatant of the producer cells was used to transduce Epstein-Barr virus-transformed B (EBV-B) cells, established from B cells of p47phox-deficient CGD patients, as an in vitro model of gene therapy for p47phox-deficient CGD. The transduced cells expressed both P-glycoprotein and p47phox protein, and the expression levels were increased after appropriate vincristine selection. The levels of superoxide production in the vincristine-selected cells were increased to a level similar to normal EBV-B cells. This result suggests that it is possible to achieve 100% correction of the CGD defect in p47phox-deficient EBV-B cells by using the bicistronic vector. This strategy could be employed not only in vitro, but also in vivo, in the gene therapy of a number of inherited diseases.
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PMID:Drug-selected complete restoration of superoxide generation in Epstein-Barr virus-transformed B cells from p47phox-deficient chronic granulomatous disease patients by using a bicistronic retrovirus vector encoding a human multi-drug resistance gene (MDR1) and the p47phox gene. 985 84

T-cell lymphomas are a biologically heterogeneous group of diseases with varying clinical presentations and outcomes. We tried to understand the effect of Epstein-Barr virus (EBV) on lymphogenesis, prognostic factors and drug resistance of T-cell lymphomas, and to establish their relationship with international prognostic factors. Formalin-fixed paraffin-embedded tissue sections from 35 patients (12 women and 23 men) with T-cell lymphomas were examined to detect the presence of EBV using RNA in situ hybridization for EBV-encoded small nuclear RNA (EBER) 1/2 and immunohistochemical stain for latent membrane protein (LMP)-1. We also tried to establish the expression of p53 and P-glycoprotein (P-gp) using immunohistochemistry. The distribution according to the subgroup was: two T-lymphoblastic lymphomas, 13 NK/T-cell lymphomas, one angioimmunoblastic T-cell lymphoma, 17 peripheral T-cell lymphomas, unspecified, and two anaplastic large cell lymphomas. The EBER was detected in 15 of 35 T-cell lymphomas (42.9%) and among these it was detected in five of 17 nodal lymphomas (29.4%) and 10 of 18 extranodal lymphomas (55.6%). There was close correlation between EBER positivity and NK/T-cell lymphoma (P = 0.032). Expression of LMP was found in a proportion of tumor cells in seven of the 15 EBER-positive cases (46.7%). There was no correlation between EBER expression and complete response (CR rate), but coexpression of EBER and p53 was associated with treatment failure (P = 0.047). The 18 patients (51.4%) with p53 expression had significantly poorer outcomes compared with the 17 patients without p53 expression (CR rate, P < 0.0005; overall survival, P = 0.0102). Twenty of 35 patients (57.1%) were positive for P-gp expression. P-gp expression was significantly associated with treatment failure (P = 0.001) and overall survival (P = 0.0089). Seventeen of 35 patients (48.6%) treated with systemic chemotherapy or radiation therapy achieved a CR after initial treatment. When the prognostic factors were grouped using the international prognostic index, the CR rate was 58.8% for the low risk group, 50.0% for the low-intermediate risk group, 14.3% for the high-intermediate risk group, and 0% for the high risk group. In conclusion, high incidence of EBV was detected among Korean patients with T-cell lymphomas. Our study supports the prediction that patients who express p53 and P-gp have a poorer prognosis than those who do not and this should be considered when treatment strategies for individual patients are selected.
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PMID:Epstein-Barr virus infection, drug resistance and prognosis in Korean T- and NK-cell lymphomas. 1142 93

Epstein-Barr virus (EBV)-associated nasal T/natural killer (NK) cell lymphoma has often been reported in Asian countries and has been recently confirmed as a novel clinicopathological entity. The prognosis of advanced stage disease is quite poor and an effective chemotherapeutic modality is strongly advocated. We have established the novel cell line NK-YS, which preserves the original characteristics of EBV-associated nasal angiocentric T/NK cell lymphoma. Using this cell line, we investigated the induction of apoptosis by apoptosis-inducing agents, and expression of P-glycoprotein (P-gp), p53 and bcl-2 proteins. NK-YS showed resistance towards apoptosis-inducing agents and expressed bcl-2 and P-gp but not p53. To overcome this drug resistance, we added cyclosporine A (CsA) and these agents to culture media as a P-gp antagonist. The combination of CsA and etoposide or CsA and doxorubicin induced apoptotic cell death. These results indicated that P-gp-mediated drug resistance is an essential mechanism of drug resistance of the NK-YS cell line. Combined therapy of conventional anti-cancer agents with CsA may have an important place in the establishment of a curative therapy for disseminated nasal angiocentric NK cell lymphoma.
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PMID:In vitro induction of apoptosis for nasal angiocentric natural killer cell lymphoma-derived cell line, NK-YS, by etoposide and cyclosporine A. 1144 96

Natural killer (NK) cells are lymphocytes with large granular lymphocyte morphology, CD3-CD56+ phenotype, non-MHC-restricted cytotoxicity, and germ-line configuration T-cell receptor genes. Two types of lymphomas originating from NK cells have been described; blastic NK-cell lymphoma, and nasal-type NK-cell lymphoma. Because recent reports indicate that blastic NK-cell lymphoma originates from the precursors of plasmacytoid dendritic cells, I will focus mainly on nasal-type NK-cell lymphoma, and discuss its pathogenesis, diagnostic problems, treatment strategy, and outcome. Nasal-type NK-cell lymphoma develops mostly in the nasal cavity and rarely in other sites, such as the skin and intestinal tract. Epstein-Barr virus (EBV) is found in lymphoma cells of almost all the patients, and is considered to be the etiologic agent. Indeed, EBV easily infects NK cells in the absence of CD21 antigen, or EBV receptor, on the surface of NK cells. Further, various types of oncogenes and suppressor oncogenes are found to be involved in its pathogenesis. Based on the data obtained from paraffin-embedded specimens, it is difficult to determine whether the lymphoma cells are of T-cell or NK-cell lineage, because immunohistochemical staining of cytoplasmic CD3 is positive both in T and NK cells, and CD56 is positive in a part of T cells. The presence of CD5 antigen indicates T-cell lineage. When the disease is limited, radiation therapy is effective, but not satisfactory. A new trial to use simultaneously both radiation and chemotherapy has started in Japan. In advanced stages, a combination chemotherapy including L-asparaginase seems to be promising, and high-dose chemotherapy with autologous or allogeneic stem cell support is under investigation. A recent report described the expression of short-length P-glycoprotein (P-gp), but not full-length P-gp in NK cells, and this mini-P-gp is unable to extrude daunorubicin. These findings may change the treatment strategy. Finally, I will present the results on interim analysis of 166 cases of nasal-type NK-cell lymphoma collected in Japan between 1994 and 1998.
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PMID:NK cell lymphoma. 1243 Sep 11

Thirty patients with nasal natural killer (NK)/T-cell lymphoma, who underwent systemic chemotherapy with or without involved-field radiotherapy between 1993 and 1998, were retrospectively reviewed to determine the clinical significance of P-glycoprotein immunohistochemically identified in tumor specimens. Eighty percent of previously untreated patients expressed P-glycoprotein. According to P-glycoprotein immunoreactivity, all patients with nasal NK/T-cell lymphoma were divided into 2 groups; (a) P-glycoprotein-negative group (N = 6) and (b) P-glycoprotein-positive group (N = 24). There was no significant difference in clinical profiles between both groups. Regardless of the P-glycoprotein expressions, Epstein-Barr virus genomes were almost identically detected in patients of the 2 groups. Contrary to our expectations, however, P-glycoprotein expressions were not found to be a strong predictor of chemotherapy resistance. Although 2 (33%) of 6 P-glycoprotein-negative patients and 10 (42%) of the 24 P-glycoprotein-positive patients showed a favorable response to systemic chemotherapy, 4 (67%) of 6 P-glycoprotein-negative patients did not achieve complete response (CR) to chemotherapy, which led to an early death, whereas 4 (17%) of the 24 P-glycoprotein-positive patients achieved CR to chemotherapy despite positive P-glycoprotein immunoreactivity. Overall, there were no significant differences in either CR rate or the response rate of patients in the two groups. Overall 5-year actuarial survival and disease-free survival for all patients were 44% and 47%, respectively, but no differences in survival rates were observed between 2 groups. (5-year actuarial survival rate: 33% for the P-glycoprotein-negative, 50% for the P-glycoprotein-positive) (P = 0.7093, log-rank). On univariate and multivariate analyses, P-glycoprotein expressions by immunohistochemical study were not found to be an important prognostic factor. Given these observations, we conclude that the molecular mechanisms of resistance to chemotherapy in nasal NK/T-cell lymphoma patients are not entirely dependent on P-glycoprotein, and that other complex mechanisms of drug action and resistance may be likely to be involved.
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PMID:Lack of correlation between P-glycoprotein and chemotherapy resistance in nasal NK/T-cell lymphomas. 1522 47

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.
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PMID:Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. 1829 94

Aplastic anemia is a rare complication of allopurinol use. We report an unusual case of aplastic anemia associated with allopurinol therapy for hyperuricemia in a patient with chronic kidney disease. A 37-year-old female patient diagnosed with Stage III chronic kidney disease was admitted with pancytopenia. She had a history of taking allopurinol for 5 months. Her bone marrow showed extremely decreased cellularity (< 20%) and there was no malignant cell infiltration. She was free of infections, including parvovirus B19, cytomegalovirus and Epstein-Barr virus. These results suggested a diagnosis of aplastic anemia. Allopurinol was discontinued immediately and treatment with blood transfusions and prednisolone was begun. After 6 months, the bone marrow cellularity improved to approximately 70%. Recently, it was suggested that decreased activity of multidrug resistance P-glycoprotein may play a role in acquired aplastic anemia. So we measured the inhibitory effect of allopurinol and oxypurinol on P-glycoprotein activity. But neither allopurinol nor oxypurinol inhibited P-glycoprotein activity.
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PMID:Allopurinol-induced aplastic anemia in a patient with chronic kidney disease. 1920 17

Membrane-bound transporter proteins play an important role in the efflux of drugs from cells and can significantly influence the pharmacokinetics of drug molecules. This study describes the production of large amounts of high-activity transporter membrane vesicles from human embryonic kidney 293-Epstein-Barr virus nuclear antigen cells transiently transfected using a Gateway-adapted pCEP4 plasmid. Transfections were scaled up to 10-liter cell cultures, and vesicle preparations were optimized using ultracentrifugation with a sucrose cushion, which enabled us to produce hundreds of milligrams of membrane vesicles expressing human efflux transporter proteins P-glycoprotein (P-gp)/multidrug resistance 1 (ABCB1), multidrug resistance protein 2 (MRP2) (ABCC2), and breast cancer resistance protein (BCRP) (ABCG2). Assays were developed and optimized for analyzing the ATP-dependent functionality of the transporters using probe substrates and specific inhibitors. Excellent signal/noise ratios of ATP-stimulated uptake for P-gp, MRP2, and BCRP vesicles were obtained, indicating high expression of functioning transporters. The uptake kinetics of the transporters was investigated by determining K(m) and V(max) using the model substrates N-methylquinidine (P-gp), estradiol-17beta-glucuronide (MRP2), and estrone-3-sulfate (BCRP). The ATP-dependent transport was inhibited by the model inhibitors verapamil (P-gp), benzbromarone (MRP2), and sulfasalazine (BCRP). The vesicles are thus well suited to screen for possible substrates and inhibitors in high throughput systems or are used for detailed mechanistic investigations of transporter kinetics of specific substances.
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PMID:High-activity p-glycoprotein, multidrug resistance protein 2, and breast cancer resistance protein membrane vesicles prepared from transiently transfected human embryonic kidney 293-epstein-barr virus nuclear antigen cells. 2007 52


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