Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid hormones cause apoptosis in the murine T-lymphoma cell line WEHI-7. Glucocorticoid receptors in these cells are cytoplasmic proteins that translocate to the nucleus upon binding hormone. Thus, regulation of cytoplasmic glucocorticoid concentrations controls the level of activated receptors and sensitivity to steroid-induced apoptosis. We found that expression of the mdr1 P-glycoprotein gene produces a reduced accumulation of dexamethasone in WEHI-7 cells. Concomitantly, there is a suppression of dexamethasone-induced changes in transcription and a decrease in steroid sensitivity. P-glycoproteins are known to cause an outward, ATP-dependent transport of a variety of unrelated hydrophobic drugs across the plasma membrane. Our results indicate that glucocorticoid transport by P-glycoproteins depends upon the presence of an hydroxyl group at position 11 of corticosteroids and is enhanced by hydroxyl groups at the positions 16, 17, and 21. The antiprogestin RU486, which contains a dimethyl aminophenyl substitution at the position 11, is not transported by the mdr1 P-glycoprotein. We have found that RU486 is an inhibitor of P-glycoprotein function, indicating that steroid analogs could be useful chemosensitizers in patients undergoing chemotherapy.
 ...
PMID:Expression of the mdr1 P-glycoprotein gene: a mechanism of escape from glucocorticoid-induced apoptosis. 765 29

Two proteins with M(r) values of 170 kDa and 200 kDa, respectively, were identified in HOB1 lymphoma cells resistant to 1.0 microM vincristine (designated HOB1/VCR1.0) by Western blot. Using anti-P-glycoprotein monoclonal antibody to immunoprecipitate the protein from the 32P-labeled extract of HOB1/VCR1.0 cells, the major form of the protein was in the area of 200 kDa. When the cells were cultured in 0.5 microM vincristine for 72 h, the major form shifted to the area of 170 kDa. Northern blot analysis of the mdr transcription showed the gene had been overexpressed to a maximum in the cells resistant to 0.5 microM vincristine. [3H]Vincristine uptake study showed the cells with hyperphosphorylated P-glycoprotein accumulated only half the amount of the agent after 60 min of incubation as compared with those with hypophosphorylated protein. The current study suggests hyperphosphorylated P-glycoprotein is a form by which the cells can effectively exploit the protein when it can not be induced any more.
 ...
PMID:P-glycoprotein is hyperphosphorylated in multidrug resistant HOB1 lymphoma cells treated with overdose of vincristine. 765 66

Drug resistance is a common phenomenon in clinical oncology. In vitro, tamoxifen has been shown to be an effective inhibitor of P-glycoprotein and a modulator of the multidrug resistance phenotype. We have previously shown that vinblastine can be given safely in combination with tamoxifen at doses that may modulate P-glycoprotein activity. In this phase I trial, tamoxifen (150 mg/m2 twice a day) was given with CHOPE (cyclophosphamide/doxorubicin/vincristine/prednisone/etoposide) in order to assess the toxicities of the combination. Resistance to three of these cytotoxic agents (doxorubicin, vincristine, and etoposide) may be mediated by P-glycoprotein. A total of 13 patients were evaluable on this trial, which showed that the maximum tolerated doses of cyclophosphamide and etoposide were 750 and 80 mg/m2, respectively. The dose-limiting toxicity was myelosuppression with 50% of the patients (3/6) treated at this dose level developing febrile neutropenia and 85% (6/7) developing grade 4 neutropenia. Tamoxifen at a dose of 150 mg/m2 twice a day can be given safely with the lymphoma regimen CHOPE at standard doses, but this combination may result in increased myelosuppression.
 ...
PMID:A phase I trial of high-dose oral tamoxifen and CHOPE. 772 Jan 78

One of the most exciting areas in clinical oncology today is the translation of laboratory research in drug resistance into therapeutic tools to improve responses to antineoplastic drugs. Two areas of investigation are currently under study in both the laboratory and clinic: reversal of gluthathione-mediated resistance and of P-glycoprotein mediated resistance. Studies are directed toward determining the role of the resistance mechanism in cancer, and toward its reversal. Increased expression of gluthathione and related enzymes, such as the gluthathione S-transferases, has been shown in human tumor samples. Phase I clinical studies with buthionine sulfoxime (BSO) have shown that gluthathione can be depleted without undue normal tissue toxicity. Now, clinical studies are underway evaluating the ability of BSO to enhance the efficacy of chemotherapy. Expression of P-glycoprotein has been described in human tumors, with increased levels observed after natural product chemotherapy in some malignancies. Studies with P-glycoprotein antagonists have been conducted in leukemia, lymphoma, multiple myeloma and in a variety of advanced malignancies. These studies have employed "first generation" antagonists such as verapamil and cyclosporine which were toxic at concentrations needed to block P-glycoprotein. Currently, studies are underway with "second generation" antagonists such as the dex stereoisomer of verapamil and the cyclosporine analogue, PSC 833. These agents may help determine the role of P-glycoprotein in clinical drug resistance. Together, these studies are aimed toward improving chemotherapeutic sensitivity in human cancer.
 ...
PMID:Chemoresistance in the clinic: overview 1994. 772 60

P-glycoprotein (Pgp), Glutathione (GSH), Glutathione S-Transferase (GST), and O6-Alkylguanine-DNA Alkyltransferase (ATase) were measured in parallel as putative indicators of drug resistance in adult leukemia. The patterns of resistance parameter expression of chronic and acute leukemia were different. In acute leukemia on average all parameters were increased as compared to normal bone marrow. In chronic leukemia GSH and GST were increased, whereas Atase, GPx and frequency of Pgp-expression were low. Treatment with cytostatic drugs did not influence median levels of expression/activity of the resistance parameters. Resistance parameter expression/activity of leukemic cells was also compared with various other tissue and tumor types. Generally the pattern of resistance parameter expression reflected the resistance status of the tissue, constitutively resistant tumor types and their corresponding normal tissue on average having higher levels than leukemic cells and other tissue and tumor types with acquired resistance. For individual patients with acute leukemia, however, none of the parameters was directly correlated with response to treatment.
Leuk Lymphoma 1995 Mar
PMID:Patterns of drug resistance parameters in adult leukemia. 777 47

A multidrug-resistant lymphoma cell line resistant to 1.0 microM vincristine (designated HOB1/VCR1.0) was established. The tubulins of parental and resistant cell lines were purified by ion-exchange chromatography. Two-dimensional polyacrylamide gel electrophoresis of tubulins showed a decrease in the basic component of beta-tubulin in the HOB1/VCR1.0 cell line; native isoelectric focusing of tubulins showed decreased expression of two more basic tubulin dimers in the same cell line. The [3H]vincristine-tubulin binding studies were performed by filtration and HPLC and displayed the tubulin of HOB1/VCR1.0 cells having a weaker binding affinity to vincristine than those of parental HOB1 and HOB1/VCR0.5 cells. The binding constant Ka of purified tubulin to vincristine, calculated from the slope of the Scatchard curve, for parental HOB1 cells was 5.6 x 10(6), and that for HOB1/VCR1.0 cells was 3.1 x 10(6). The Scatchard kinetics was also used to determine the binding ability of the purified tubulins to [3H]colcemid: the Kas for parental and HOB1/VCR1.0 cells were 3.9 x 10(5) and 2.0 x 10(5), respectively. The current study suggests that high-level resistant cells, HOB1/VCR1.0, tend to express fewer tubulin isoforms of stronger binding affinities to antimitotic agents; that is, they preserve weak drug-binding forms rather than produce additional species. This may be a mechanism for the cells to protect themselves from drug injury when the P-glycoprotein cannot efficiently pump out the agent of high concentration within the cells.
 ...
PMID:Purification and characterization of tubulin from parental and vincristine-resistant HOB1 lymphoma cells. 778 33

To optimize the immunohistochemical detection of the multidrug resistance (MDR)-associated P-glycoprotein (P-gp) in chronic lymphoid disorders, the authors compared the sensitivity of three different monoclonal antibodies (MoAb) directed against P-gp (C219, JSB-1, and MRK 16) by using the APAAP technique on four tissue preparations obtained from lymphoid tumors: Cryostat sections, ModAMEX processed sections, frozen cytospin preparations, and fresh cytospin preparations. Tumor samples were obtained from patients with previously treated chronic lymphocytic leukemia (6 cases) or non-Hodgkin's malignant lymphoma (4 cases). Lymph nodes (n = 9), spleen (n = 3), and blood (n = 5) were analyzed. JSB-1 MoAb detected P-gp in 4 of 12 cases (33.3%) on either frozen sections or ModAMEX processed sections, and in 6 of 17 cases (35.3%) on frozen cytospin preparations. The sensitivity of JSB-1 was significantly improved when fresh cytospin preparations were used with an incidence of P-gp positive samples as high as 70.6% (P < .05). C219 MoAb was unreactive with lymphoid cells whatever the technique used, whereas this antibody stained stromal cells. MRK 16 MoAb was equally reactive to JSB-1 on fresh cytospin preparations, but unreactive when the other preparations were used. The specificity of JSB1 MoAb was confirmed by both Western blot analysis and Rhodamine 123 efflux assay. The authors used JSB-1 MoAb on fresh cytospin smears prepared from 28 CLL patients. Overall incidence of P-gp positive cases was 39.2%. Univariate analysis showed that P-gp expression was correlated with prior therapy, refractoriness to treatment, Rai stratification, and time of tissue storage after diagnosis. The authors recommend the use of JSB-1 on fresh cytospin preparations for the immunocytochemical detection of P-gp in chronic lymphoid disorders.
 ...
PMID:Optimization of immunohistochemical detection of P-glycoprotein in chronic lymphoid disorders. 780 2

A multidrug-resistant (MDR) cell line isolated from HOB1 lymphoma cells was characterized. The MDR phenotype in this cell line was typified by resistance to vincristine with varying degrees of cross-resistance to Adriamycin, colcemid and actinomycin D. Decreased intracellular [3H]vincristine with concurrent increase in the expression of a 170-kDa membrane glycoprotein (P-glycoprotein) suggested a plausible underlying mechanism for the development of resistance. Amplification of the mdr1 gene as well as a homogeneous staining region on the long arm of the 7th chromosome was observed. Moreover, metabolic studies with [14C]glucosamine or [14C]mannose indicated differential expressions of membrane glycoproteins between the drug-sensitive parental and drug-resistant descendant cells. It is concluded that the development of drug resistance in HOB1 lymphoma cells was strongly correlated with the overexpression of P-glycoprotein.
 ...
PMID:Characterization of vincristine-resistant HOB1 lymphoma cell line showing the classical MDR phenotype and altered expression of membrane glycoproteins. 790 40

In order to assess the clinical role of the MDR1 gene in chronic lymphocytic leukemia (CLL), we determined its expression in the leukemic cells of 39 patients with CLL and compared this with other clinical and laboratory parameters. MDR1 RNA expression was detected in 29 patients. MDR1 RNA transcripts were independent of age, treatment status of the patients and the clinical stage of CLL, but correlated with the white blood cell count and MDR2 RNA transcripts. Expression of the tumor suppressor gene p53 was found in 30 out of 37 patients and was associated with MDR1 RNA expression (P < 0.001). Immunocytochemistry using the monoclonal antibody C219 was performed in 38 patients, and in 28 cases, more than 5% of the leukemic cells were found to express cell surface P-glycoprotein. P-glycoprotein expression correlated with the expression of MDR1 RNA (P = 0.048).
Leuk Lymphoma 1994 Apr
PMID:MDR1 gene expression in chronic lymphocytic leukemia. 791 28

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.
 ...
PMID:Retinoic acid-induced apoptosis and regression of a refractory Epstein-Barr virus-containing T cell lymphoma expressing multidrug-resistance phenotypes. 791 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>