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

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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)

Multiple selections with either vinblastine or vincristine in the human ovarian carcinoma cell line SKOV3 resulted in variants with increasing degrees of multidrug resistance. SKOV3 derivatives that span a wide range in resistance (4- to 2000-fold) were obtained and analyzed for P-glycoprotein expression. In general, we observed a progressive increase in P-glycoprotein level (detected by Western blot) that paralleled the increase in multidrug resistance. However, a more detailed analysis of the P-glycoprotein mRNA and gene level indicated that the amount of P-glycoprotein expressed may be under complex control. At low levels of resistance, only an increase in P-glycoprotein mRNA and protein was observed. At intermediate to high levels of resistance P-glycoprotein gene amplification became evident. At the high level of resistance, an example was observed where only the amount of P-glycoprotein was increased without a concomitant increase in mRNA or gene copy. The mechanisms through which the content of P-glycoprotein in the plasma membrane is mediated are not understood; it is possible that the resistant variants identified here represent perturbations at different levels of regulation.
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PMID:P-glycoprotein expression in multidrug-resistant human ovarian carcinoma cell lines. 256 64

An overexpression of plasma membrane 170-180 kDa P-glycoproteins is consistently found in multidrug-resistant (MDR) cell lines. In this study MRK-16, a monoclonal antibody (mAb) reacting with P-glycoprotein is used to study the putative functional role of this protein in vincristine (VCR) and daunorubicin (DNR) cellular accumulation in the MDR human ovarian carcinoma cell line 2780AD. We established that this cell line is highly cross-resistant to vincristine and daunomycin, related to a greatly reduced drug accumulation. Verapamil (Vp) (8 microM) caused a 3.6-fold increase in DNR as well as VCR accumulation. Exposition of 2780AD cells to MRK-16 led to an increase of 30% in cellular accumulation of VCR, both in normal growth medium as well as in medium without added glucose and with sodium azide, which largely depleted cellular ATP levels. No increase in DNR accumulation was found under these conditions. However, in the presence of 8 microM Vp, MRK-16 increased not only VCR but also DNR accumulation with about 30%. The relative increase of DNR accumulation was constant in a concentration range of 0.2-4 microM DNR. These data indicate that mAbs against P-glycoprotein might potentiate the action of calcium antagonists like Vp to increase cellular anthracycline accumulation.
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PMID:Increase of daunorubicin and vincristine accumulation in multidrug resistant human ovarian carcinoma cells by a monoclonal antibody reacting with P-glycoprotein. 289 43

Multidrug resistance (MDR) is associated with overproduction of Mr 170,000 membrane proteins (P-glycoproteins) caused by either gene amplification, transcriptional activation, or both. In rodents the amplified domain comprises genes that encode P-glycoproteins and at least five unrelated genes, one of which encodes the calcium-binding protein sorcin. The amplification and increased expression of these genes always includes one P-glycoprotein-encoding gene (pgp1 in hamsters, homologous to mdr1 in humans). In human MDR cells only elevated mdr1 expression has been shown thusfar, although another P-glycoprotein encoding gene (mdr3, homologous to hamster pgp3) is closely linked. Here we show that the human homolog of the hamster sorcin gene resides on chromosome 7 like the P-glycoprotein-encoding genes. Furthermore, gene classes designated 4, 5, and 6 are coamplified with mdr1 and mdr3 in the human ovarian carcinoma cell line 2780AD, which strongly suggests that the overall structure of the human MDR domain is the same as in rodents. Class 6 was moderately and mdr1 was highly overexpressed in this cell line. Four other human MDR cell lines also have much higher mdr1 overexpression than expected from the relatively low levels (2- to 30-fold) of gene amplification. This contrasts with the results of previous work with rodent MDR cells, in which the increase in P-glycoprotein mRNA levels usually parallels the increase in gene copy number. Although four of the five human MDR cell lines have coamplified mdr3, its expression was undetectable. Our results confirm the central role of the mdr1 (pgp1) gene in MDR and suggest that different cross-resistance patterns are not due to differential expression of different P-glycoprotein genes.
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PMID:Genes amplified and overexpressed in human multidrug-resistant cell lines. 290 6

P-glycoprotein, a molecular weight 170 kilodalton membrane component can be accurately detected in a series of human ovarian carcinoma cells with increasing degrees of multidrug resistance by using a modified immunoperoxidase "sandwich" method. Drug-resistant derivatives were selected from a drug-sensitive parent ovarian carcinoma cell line, SKOV3, by continuous exposure to increasing concentrations of the cytotoxic drug vincristine. These cells had corresponding overexpression of P-glycoprotein demonstrable at both protein and mRNA levels. Monoclonal antibodies against P-glycoprotein localized staining for P-glycoprotein to the plasma membrane and the Golgi region in individual drug-resistant cells, in proportion to their P-glycoprotein expression. P-glycoprotein was not demonstrable in drug-sensitive SKOV3 cells by either immunoblotting or immunocytochemical staining methods. The immunocytochemical staining method allowed detection of P-glycoprotein in the least drug-resistant cell line with as low as 8-fold relative resistance to vincristine. This method is as sensitive as Northern blot, and more sensitive than standard Western blot in detection of P-glycoprotein. We conclude that this highly sensitive immunocytochemical staining method for P-glycoprotein can be suitable for determination of P-glycoprotein expression in biopsy samples of tumors, and it can be a powerful diagnostic and prognostic tool in the study of the natural history of drug resistance. This may have important applications in the clinical management of cancer chemotherapy.
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PMID:A sensitive method for immunocytochemical detection of P-glycoprotein in multidrug-resistant human ovarian carcinoma cell lines. 290 10

We have successfully transferred and cloned a fragment of a human multidrug-resistant gene by using DNA-mediated gene transfer. Macromolecular DNA of human multidrug-resistant K562 cells was transfected to drug-sensitive mouse Ltk- cells to obtain a drug-resistant transfectant with a human resistant gene. Both primary and secondary transfectants showed similar patterns of cross-resistance to Adriamycin and vincristine. The mechanism of drug resistance of the transfectants was attributed to decreased retention of the drug. Three secondary transfectants obtained independently contained common Alu-containing EcoRI fragments 15, 6.5, 3.7, 2.6, and 1.9 kilobases long. The 2.6-kilobase EcoRI fragment was cloned from a lambda phage genomic library made from DNA of a secondary transfectant. The 2.6-kilobase fragment was detected in the primary and secondary transfectants but not in the parental Ltk-, Adriamycin-resistant Ltk-, and Adriamycin-resistant P388 cells. This sequence was found to be amplified in several multidrug-resistant cell lines such as Adriamycin-resistant ovarian carcinoma A2780 and colchicine-resistant KB carcinoma cells. The 2.6-kilobase fragment hybridized with a 4.5-kilobase mRNA which is overexpressed in the Adriamycin-resistant K562 cells and the Adriamycin-resistant A2780 cells but not detected in the parental K562 cells. The gene transferred and cloned in this study seems to be related to the P-glycoprotein gene as judged from the size of mRNA and its overexpression in some of the multidrug-resistant cell lines where P-glycoprotein was found to be highly expressed.
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PMID:DNA-mediated transfer and cloning of a human multidrug-resistant gene of adriamycin-resistant myelogenous leukemia K562. 303 11

2',2'-Difluorodeoxycytidine (gemcitabine; dFdC) is a nucleoside analog with promising antitumor activity. To be active it must be phosphorylated by deoxycytidine kinase (dCK). We induced resistance to gemcitabine in the human ovarian carcinoma cell line A2780 by exposure to increasing concentrations of gemcitabine. At 72 hours' exposure the IC50, defined as the concentration of gemcitabine causing 50% growth inhibition, increased from 0.6 nmol/L gemcitabine in A2780 to 92 mumol/L in the resistant variant, AG6000. AG6000 is cross-resistant to other drugs that require activation by dCK, such as I-beta-D-arabinofuranosylcytosine, 5-aza-2'-deoxycytidine, and 2-chlorodeoxyadenosine. AG6000 was also cross-resistant to 2',2'-difluorodeoxyuridine (dFdU), the deamination product of gemcitabine. In addition, cross-resistance to the multidrug-resistance drugs doxorubicin and vincristine was observed. This was not associated with induction of P-glycoprotein. No accumulation of gemcitabine triphosphate could be detected in AG6000 cells, in contrast to the parental A2780 cells. There was no specific dCK activity in extracts from AG6000 cells. Western blot analysis using a polyclonal anti-dCK antibody did not reveal any dCK protein in AG6000 cell extracts. Reverse transcribed and polymerase chain reaction amplified mRNA, using specific dCK primers, demonstrated that AG6000 expressed a normal length amplicon of 701 base pairs, besides an aberrant amplicon of 500 base pairs. Although the resistant cell line is routinely cultured in 6 mumol/L gemcitabine, the resistant phenotype can be maintained for at least 10 passages without gemcitabine. These results indicate that the gemcitabine resistance phenotype is stable and mainly due to dCK deficiency.
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PMID:Induction of resistance to 2',2'-difluorodeoxycytidine in the human ovarian cancer cell line A2780. 748 43

Using viable adriamycin resistant human ovarian carcinoma cells 2780AD and colchicine resistant human oral epidermoid carcinoma cells KB-24 as the immunogen in primary and subsequent i.p. immunizations, followed by i.v. boostings with crude plasma membranes of 2780AD, KB-24, Chinese hamster lung cells resistant to vincristine DC-3F/VCRd-5L, and resistant to daunorubicin DC-3F/DMXX, we have generated a new murine monoclonal antibody (McAb), designated F4, of IgG1 isotype. McAb F4 reacted strongly with a cell surface epitope of drug resistant cells and insignificantly with their drug sensitive counterparts. Cell surface localization of F4 epitope was determined by immunofluorescence and laser scanning confocal imaging system. Results obtained from immunoprecipitation and immunoblot analyses using F4 and mdr1 P-glycoprotein specific McAb JSB-1 demonstrated the reactivity of P-glycoprotein with F4. These results along with those obtained from competitive binding-inhibition, chemical modification, and enzyme hydrolysis, revealed that McAb F4 detects an extracellular epitope of P-glycoprotein, and is different from other major McAbs directed against P-glycoprotein, e.g. C219, MRK16, JSB-1, HYB-241 and C494. Deduced from the putative structure of mdr1 protein and its orientation in cell membrane, it is proposed that F4 epitope is localized in or near the 3rd, and/or 6th extracellular transmembrane loops of P-glycoprotein.
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PMID:Characterization of a new monoclonal antibody F4 detecting cell surface epitope and P-glycoprotein in drug-resistant human tumor cell lines. 750 40

Resistance to chemotherapy is the major obstacle to controlling malignant tumors. To characterize multidrug resistance phenotype in human primary ovarian cancer without chemotherapy, expressions of the mdr1 gene in 52 cases of ovarian cancer (44 common epithelial, 5 nonepithelial, and 3 metastatic cancers) were analyzed by polymerase chain reaction of RNA after reverse transcription. Furthermore, localization of P-glycoprotein, which is encoded by the mdr1 gene, was studied immunohistochemically. Although overall expression of the mdr1 gene was relatively low, its expression level was the highest in well-differentiated cancer tissues. Serous and mucinous adenocarcinomas showed higher levels of expression compared with clear cell and endometrioid carcinomas. P-glycoprotein was positive on luminal surfaces of lining cells of ovarian cancer and on those of inclusion cysts from which epithelial ovarian cancer is considered to develop. Thus, some ovarian cancer cases before chemotherapy are intrinsically multidrug resistant, which can be determined by mdr1 gene expression, and this phenotype should be taken into account for effective chemotherapy of ovarian epithelial carcinomas.
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PMID:Expression of multidrug resistance gene and localization of P-glycoprotein in human primary ovarian cancer. 750 19

The aim of the study is to review the mechanisms of resistance to four classes of drugs that are widely used in ovarian carcinoma: platinum (cisplatin/carboplatin) compounds, classical alkylating agents (cyclophosphamide/melphalan), natural drugs (doxorubicin), and "new drugs" (taxol and taxotere). Both platinum and classical alkylating agents mediate their cytotoxicity by the formation of drug-DNA adducts, resulting in DNA damage. Therefore, drug resistance mechanisms are (in part) comparable. In ovarian carcinoma cell lines increased repair of DNA damage and increased detoxification by binding of drugs to glutathione, possibly catalyzed by glutathione S-transferases, have been identified as the most prominent resistance mechanisms to these drugs. Studies on the role of DNA repair mechanisms and glutathione in human ovarian carcinoma are hampered by the complexity of enzyme systems involved in DNA repair and intratumor heterogeneity for glutathione. Resistance to doxorubicin appears to be mediated by enhanced efflux from the cell by increased expression of membrane glycoproteins acting as a drug efflux pump, such as P-glycoprotein. Resistance to doxorubicin can also be due to quantitative and/or qualitative changes in the nuclear target of doxorubicin, topisomerase (Topo) II. Finally, resistance to taxol may be mediated by enhanced expression of P-glycoprotein, while presumed other mechanisms such as alterations in tubulin structure, the cellular "target" of taxol, and changes in polymerization of tubulin are still largely unresolved. Several ways to modulate the reviewed resistance mechanisms are also described. In conclusion, this review shows that many cell biological factors may be involved in drug resistance. The relevance of the identification of most of these factors in ovarian carcinoma patients however remains to be established.
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PMID:Cell biological markers of drug resistance in ovarian carcinoma. 762 1

A multidrug-resistant cell line (A2780/ADM) of human ovarian carcinoma which can resist 0.8 microgram.ml-1 of adriamycin (ADM) was obtained by step-wise selection exposure to increasing doses of ADM. A2780/ADM cells showed 17-fold higher resistance to ADM than A2780 cells. The doubling times were 43.8 h in A2780/ADM and 26.3 h in A2780 cells. Colony formation rates were 15%-20% in A2780/ADM and 65%-75% in A2780 cells. A2780/ADM cell line was also shown to significantly cross-resistant to vincristine (VCR) and VP-16, but no cross-resistance was found to 5-Fu, PDD or Mel. A further investigation showed that intracellular accumulation of ADM in A2780/ADM was significantly decreased. Expressions of P-glycoprotein and GST-pi were increased in A2780/ADM by means of immunohistochemical method. Verapamil (Ver) combined with ADM was found to increase the sensitivity and reverse the resistance to ADM in A2780/ADM. This study indicates that A2780 ADM has the peculiarity of multidrug resistance and there may be other mechanism of drug-resistance besides MDR related to P-170.
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PMID:[Establishment of adriamycin-resistant human ovarian carcinoma cell line and its mechanism of multidrug resistance]. 766 Jul 93


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