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

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein and epidermal growth factor (EGF) receptor expression were surveyed immunohistochemically in the tissue of urogenital carcinomas including 12 renal cell carcinomas, 9 bladder transitional cell carcinomas, 2 prostate adenocarcinomas and 1 penile squamous cell carcinoma. Three bladder carcinomas and the penile carcinoma were following initial chemotherapy at the time of relapse. P-glycoprotein expression was detected in 3 of 12 renal cell carcinomas and in all recurrent carcinomas. EGF receptor was not detected in any of the specimens.
...
PMID:Detection of P-glycoprotein in human urogenital carcinomas and its relationship to epidermal growth factor receptor expression. 168 34

The mdr gene, which encodes an energy-dependent multidrug efflux pump termed P-glycoprotein, is expressed in some normal human and rodent tissues, including the adrenal gland, kidney, liver, colon, small intestine, and brain and testis capillary endothelial cells. Because of the important role played by the multidrug transporter in determining sensitivity of normal tissues and resistance of cancers to chemotherapeutic drugs, we and others have been determining the environmental factors which regulate expression of the mdr gene. In previous studies, expression of the human MDR1 gene has been shown to be regulated by heat shock, arsenite, and cadmium in a kidney carcinoma cell line, and mdr RNA is dramatically elevated in rat liver after partial hepatectomy or treatment of the animals with cytotoxic agents. We have now investigated the genetic response of the mdr gene to acute cytotoxic insults in rodent and human tissue culture cells. Following exposure to several drugs, most of which are known to be substrates for the multidrug transporter, mdr RNA levels were found to increase substantially in the rodent cells, but not the human cells. Furthermore, RNA levels for topoisomerase II, an intracellular target for these drugs, decreased in the rodent cells. These results suggest a complex pattern of regulation of mdr RNA levels, depending on animal species and cell type, and possible coordinate regulation with topoisomerase II RNA levels.
...
PMID:Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. 170 76

Drug resistance has been associated with resistance to NK- and LAK-cell-mediated cytotoxicity. We evaluated this issue in human cell lines, using multiple myeloma cells (8226) and 2 multi-drug-resistant (MDR) sublines selected using doxorubicin (8226/Dox40) and mitoxantrone (8226/MR40). In parallel, we studied the human breast carcinoma cell line series MCF7, MCF7/D40 and MCF7/Mitox. Unlike the sensitive parental cell lines, all 4 sublines display MDR-patterns of resistance, with the P-glycoprotein pump (P-170) detected only in the doxorubicin-selected sublines. Flow cytometric and immunocytochemical analyses showed expression of cellular adhesion molecules ICAM-I and LFA-3, and MHC-Class-I (MCF7/D40 only), to be decreased in the doxorubicin-selected MDR-sublines, whereas expression of CD56 (Leu 19) was strongly up-regulated in 8226/Dox40. Lysis of P-170-positive MDR tumor cells by NK or LAK cells was, however, unaffected by these alterations, suggesting redundancy in effector:target-cell adhesion pathways. Mitoxantrone-selected tumor cells did not display P-170, nor did they show altered expression of cellular adhesion molecules. Their susceptibility to NK or LAK cytolysis was also unimpaired as compared to the parental cell lines. Clinically, these results imply that immunotherapeutic modalities aiming at increased natural killer functions deserve full consideration even in patients who have become refractory to further cytostatic drug treatment.
...
PMID:Altered expression of P-glycoprotein and cellular adhesion molecules on human multi-drug-resistant tumor cells does not affect their susceptibility to NK- and LAK-mediated cytotoxicity. 171 Jun 9

The most consistantly reported alteration of multidrug-resistant carcinoma cells is the overexpression of a membrane glycoprotein, termed P-glycoprotein. In this study we examined whether the strong intrinsic chemotherapy resistance of glial tumors might be related to the expression of the MDR1 gene which codes for P-glycoprotein. Fourteen glial tumors were examined immunohistochemically using the monoclonal antibody C219. In addition, RNA samples of 11 of these tumors were analysed using a sensitive Northern blot assay. P-glycoprotein is expressed in all 14 glial tumors; the number of stained tumor cells, however, varied considerably ranging from 0.3% to 15%. There was no correlation between the number of MDR1-positive cells and the histological malignancy. Varying amounts of MDR1 mRNA were detectable in 7 from 11 examined tumors. The results of our study show that the MDR1 gene is expressed in human glial tumors and suggest that the multidrug transporter may contribute to the clinical non-responsiveness of these tumors to chemotherapy.
...
PMID:The multidrug-resistance gene MDR1 is expressed in human glial tumors. 172 31

Previously, we identified P-glycoprotein in primary gastroesophageal adenocarcinomas and in adjacent mucosa. This study is a further investigation of P-glycoprotein expression in adenocarcinomas and benign mucosa. Sixteen resection specimens were studied (seven for gastric adenocarcinoma, seven for esophageal adenocarcinoma, one for adenocarcinoma at the gastroesophageal junction, and one for severe dysplasia in Barrett's esophagus). Multiple samples of tumor and mucosa were submitted according to a specimen diagram. Lymph node and distant metastases were studied when available. P-glycoprotein expression was identified in paraffin-embedded tissues by immunohistochemistry using monoclonal antibody C219 and was scored as the percentage of cells stained. P-glycoprotein was identified in six of 16 resection specimens. Intratumoral variability of C219 score was noted in three resections. No increase in expression was identified in lymph node or distant metastases as compared with primary tumors or in the invasive margin of the tumor as compared to the center. For every case in which tumors expressed P-glycoprotein, it was also diffusely present in all types of benign gastric and Barrett's mucosa, both adjacent to and distant from (up to 8 cm) the tumor. We also studied biopsies from 10 patients with Barrett's esophagus who did not have carcinoma. P-glycoprotein was only focally present in one of the 10 biopsies. Mucosa expressing P-glycoproteins may be the substrate from which a P-glycoprotein positive tumor arises.
...
PMID:P-glycoprotein expression in gastroesophageal adenocarcinomas, their metastases, and surrounding mucosa: a mapping study. 172 84

Following EMS mutagenesis, three estramustine (EM) resistant DU 145 human prostatic carcinoma cell lines were clonally selected by exposure to incrementally increasing concentrations of the drug. Although only low levels of resistance (approximately 3-fold) were attainable, this resistance was stable in the absence of continuous drug exposure. These EM-resistant clones (EMR 4,9,12) did not exhibit cross resistance to vinblastine, taxol, or adriamycin, and had collateral sensitivity to cytochalasin B. None of the lines had elevated expression of P-glycoprotein mRNA or glutathione S-transferase activity, suggesting a phenotype distinct from the classic multi-drug resistance phenotype. This conclusion was supported further by the observation that two MDR cell lines (FLC mouse erythroleukaemic and SKOV3 human ovarian carcinoma cells) showed sensitivity to EM. Fluorescent activated cell sorting analysis of the effects of EM on cell cycle traverse revealed that at EM concentrations up to 20 microM an increasing percentage of wild type cells were blocked in G2/M; no such effect occurred in EMR lines. Differential interference contrast microscopy was employed to study EM's effect on mitosis. EMR lines were able to form functional, albeit smaller, spindles at EM concentrations that resulted in chromosomal disorganisation and inhibition of mitotic progression in wild type cells. EMR lines were able to progress through mitosis and cytokinesis at the same rate as untreated cells. Tritiated EM was used to evaluate potential drug uptake/efflux mutations in ERM clones. EMR 4 and 9 incorporate less EM than wild type cells; however, they have significantly decreased cellular volumes. The initial efflux rate constants for EMR clones were greater than for wild type cells. Within 5 min greater than 70% of the drug was lost from resistant cells compared to a 50% loss by the wild type. Although the specific mechanisms of resistance have yet to be defined, the lack of collateral resistance to other MDR/anti-microtubule agents could serve as the basis for the clinical use of EM in combination chemotherapy.
...
PMID:Resistance to the antimitotic drug estramustine is distinct from the multidrug resistant phenotype. 189 55

The resistance of malignant tumors to chemotherapy is often associated with overexpression of the multidrug resistance gene MDR. Its gene product, P-glycoprotein, acts as a drug efflux pump for chemotherapeutic agents. The authors studied MDR expression in 28 adenocarcinomas arising in Barrett's esophagus (EAs) using a monoclonal antibody directed against this gene product. The results were compared with MDR expression in 27 gastric adenocarcinomas (GAs). P-glycoprotein was detected in both tumor and normal mucosa in 7 of 27 GAs and in 6 of 10 EAs that were resected without prior chemotherapy. Chemotherapy was given before surgical resection in 18 of the EAs studied. Five patients had a partial response to chemotherapy, and one had a complete eradication of his carcinoma; all of these tumors were negative for P-glycoprotein. Of 12 patients without chemotherapy response, 6 had tumors that expressed P-glycoprotein. The authors conclude that P-glycoprotein is present in EAs and GAs before exposure to chemotherapy. The presence of P-glycoprotein in tumors usually correlates with its presence in the adjacent mucosa. Its presence in tumor cells may be an indicator of lack of sensitivity to chemotherapy.
...
PMID:Expression of a multidrug resistance gene in esophageal adenocarcinoma. Correlation with response to chemotherapy and comparison with gastric adenocarcinoma. 239 10

Studies were undertaken to identify the protein kinase(s) responsible for P-glycoprotein phosphorylation in multidrug-resistant (KB-V1) human carcinoma cells and to elucidate the functional role of phosphorylation. P-glycoprotein migrated on sodium dodecyl sulfate gels with apparent Mr 150,000 and is termed P150. When KB-V1 membrane vesicles were incubated with [gamma-32P] ATP, P150 was phosphorylated by an endogenous kinase that exhibited properties of membrane-inserted protein kinase C (PKC). Both membrane-bound P150 and purified P150 served as effective substrates for highly purified rat brain PKC which incorporated approximately 0.6 mol of phosphate/mol of P150. Enzyme assays showed that KB-V1 cells exhibit 4-fold higher PKC activity compared with the drug-sensitive KB-3 cell line. The basal phosphorylation of P150 observed in 32P-labeled cells was increased 2-fold by phorbol ester (PMA) treatment and reduced 30% by treatment with the isoquinolinsulfonamide H-7. Phosphopeptide maps of partially digested P150, phosphorylated either in vitro with PKC or in intact 32P-labeled control or PMA-stimulated cells, were indistinguishable from one another. Drug accumulation assays revealed that PMA treatment of KB-V1 cells significantly reduced [3H]vinblastine accumulation induced by verapamil or by tetrandrine. The results suggest that PKC is primarily responsible for P150 phosphorylation in KB-V1 cells and that phosphorylation may play a modulatory role in the drug transport process.
...
PMID:Protein kinase C phosphorylates P-glycoprotein in multidrug resistant human KB carcinoma cells. 197 May 71

Four pyridine analogues and their dihydropyridine counterparts were examined for their ability to reverse drug resistance in a multidrug-resistant human carcinoma cell line, KB-C2. Two pyridine analogues were more able to reverse drug resistance than their dihydropyridine counterparts. The other two pyridine analogues had an effect on drug resistance similar to their dihydropyridine counterparts. The calcium channel-blocking activity of all the pyridine analogues was considerably lower than that of the dihydropyridine analogues. Of the pyridine analogues, 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4 -(3- nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) was the most effective in reversing multidrug resistance. PAK-104P (1 and 5 microM) completely reversed the drug resistance in KB-8-5 and KB-C2 cells, respectively. The reversing effect of PAK-104P was greater than that of other multidrug resistance-reversing agents, cepharanthine, verapamil, nimodipine, and nicardipine. PAK-104P at 1 microM increased about 10-fold the accumulation of vinblastine in KB-C2 cells, whereas verapamil at the same concentration increased the accumulation about 2-fold. The inhibition of [3H]azidopine photolabeling of P-glycoprotein by the pyridine and dihydropyridine analogues except 2-[methyl(phenyl-methyl)amino]ethyl 4-(2-chlorophenyl)-5-(4-methyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-d ihydro-2,6- dimethyl-3-pyridinecarboxylate P-oxide correlated with the reversing of drug resistance by the analogues. Some newly synthesized pyridine analogues seemed to have lower calcium channel-blocking activity and more potent resistance-reversing ability than verapamil and other calcium channel blockers.
...
PMID:Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel blocking activity than their dihydropyridine counterparts. 197 Jul 52

Treatment of drug-resistant human KB carcinoma cells (KB-V1) with 0.2 microM phorbol 12-myristate 13-acetate (PMA) resulted in increases of 4-fold in both membrane-associated protein kinase C activity and phosphorylation of P-glycoprotein. The response was essentially complete after 30 min and was relatively stable, since both of these parameters remained elevated above basal levels in cells exposed to PMA for 24 hours. In contrast, long-term PMA treatment of drug-sensitive KB-3 cells caused complete depletion of protein kinase C. The rate of accumulation of [3H]vinblastine in KB-V1 cells was 0.8 +/- 0.1 pmol/mg/30 min in the absence, and 1.9 +/- 0.2 pmol/mg/30 min in the presence, of 20 microM verapamil. Preincubation of cells with PMA resulted in a time-dependent decrease, up to 60% after 24 hours, in both of these values. These results suggest that protein kinase C mediated phosphorylation stimulates the drug transport activity of P-glycoprotein.
...
PMID:Correlation of protein kinase C translocation, P-glycoprotein phosphorylation and reduced drug accumulation in multidrug resistant human KB cells. 197 16


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

---