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)

P170 (P-glycoprotein) is a membrane protein found in high levels in multidrug-resistant cultured cell lines. We have localized this protein using monoclonal antibody MRK16 by immunofluorescence and electron microscopy in the multidrug-resistant human carcinoma cell line KB-C4. The P170 determinant recognized by antibody MRK16 was found on drug-resistant KB-C4 cells, but not on parental drug-sensitive KB-3-1 cells. The determinant was present on the external surface of the plasma membrane and on the luminal side of Golgi stack membranes. P170 was excluded from coated pits at the plasma membrane and absent from endocytic vesicles and lysosomes. This determinant was detected only in small amounts in the endoplasmic reticulum. The high protein concentration of P170 in the plasma membrane is consistent with a role of this protein as a drug efflux pump at the cell surface.
J Histochem Cytochem 1987 Dec
PMID:Immunocytochemical localization of P170 at the plasma membrane of multidrug-resistant human cells. 289 Jun 86

Intrinsic and acquired multidrug resistance is an important problem in cancer therapy. Multidrug resistance results from overexpression of the MDR 1 gene, which encodes a drug-efflux pump called P-glycoprotein. We have isolated a 1-kilobase genomic fragment containing the major transcription initiation sites for the human MDR 1 gene. Ribonuclease protection experiments using this fragment indicate that normal human adrenal, colon, and liver cells, the human hepatoma cell line HepG2, and vinblastine-selected human KB multidrug-resistant cells initiate transcription of the MDR 1 gene at the same site within this fragment. The 0.43-kilobase region upstream from the major transcription initiation site linked to the chloramphenicol acetyltransferase gene showed promoter activity in CV-1 monkey kidney cells and in human KB cells. The putative promoter region has a consensus CAAT box and two GC box-like sequences, but no TATA sequence. This identification and isolation of promoter sequences for the MDR 1 gene will permit studies on how expression of this gene is regulated in normal human tissues and cancers.
J Biol Chem 1987 Dec 25
PMID:Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene. 289 92

We have determined the frequency with which Chinese hamster cells become resistant to either methotrexate or doxorubicin (former generic name, adriamycin) alone or to the two drugs simultaneously. We find that the frequency of acquisition of simultaneous resistance is 10-100 times higher than that predicted from the frequency of each resistance selected independently. In approximately 50% of cloned resistant variants, resistance is the result of amplification of the dihydrofolate reductase gene (methotrexate) and/or of the multiple-drug-resistance P-glycoprotein gene (doxorubicin). Prior exposure of cells to hypoxia markedly enhances these resistance frequencies. Our results indicate that the simultaneous emergence of resistance to these two cancer chemotherapeutic agents are not independent events, and we interpret them to constitute two consequences of the same basic process occurring at a high frequency.
Proc Natl Acad Sci U S A 1987 Dec
PMID:Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (adriamycin) resistance. 289 97

We have examined the expression of P-glycoprotein in clinical leukemic cell samples by using a monoclonal antibody (MRK16) against P-glycoprotein. We found that leukemia cells isolated from 3 out of 6 patients with blast crisis of chronic myelogenous leukemia were reactive to MRK16. These 3 cell lines expressed high levels of mdr1 mRNA, which codes for P-glycoprotein. The present result indicates that the clinically refractory state of the tumor may be predicted in part by determining P-glycoprotein expression using the monoclonal antibody against P-glycoprotein, and the mdr1 probe.
Jpn J Cancer Res 1987 Dec
PMID:Detection of multidrug resistance markers, P-glycoprotein and mdr1 mRNA, in human leukemia cells. 289 23

For the characterization of membrane changes related to Adriamycin resistance in tumor cells, we have developed monoclonal antibodies against Adriamycin-resistant human myelogenous leukemia K562 (K562/ADM). In addition to the monoclonal antibodies which recognize P-glycoprotein, we have obtained two monoclonal antibodies (designated MRK4 and MRK20) which recognize an Mr 85,000 membrane protein. Using MRK20 as a probe, we have studied the expression of the Mr 85,000 protein in various human multidrug-resistant and -sensitive cell lines. The Mr 85,000 protein was overexpressed in K562/ADM and in a human ovarian cancer cell line resistant to Adriamycin, 2780AD. The protein, if any, was not detected in other drug-resistant human cell lines such as colchicine-resistant KB cells (KB-C4), vinblastine-resistant CEM cells (CEM/VLB100), and vincristine-resistant K562 cells (K562/VCR). We have isolated subclones of K562/ADM cells which express different amounts of the Mr 85,000 protein. The expression of the Mr 85,000 protein diminished when the cells were not kept in Adriamycin, and increased when the clones were kept in the presence of Adriamycin. In contrast, the expression of P-glycoprotein remained constant whether in the presence or absence of Adriamycin during these experiments. These findings suggest that the Mr 85,000 membrane protein is closely related to the resistant mechanism specific to Adriamycin resistance, which is different from that of the pleiotropic drug resistance.
Cancer Res 1988 Dec 15
PMID:Mr 85,000 membrane protein specifically expressed in adriamycin-resistant human tumor cells. 290 93

We have examined the relationship between transformation and multidrug resistance by employing the v-H-ras or v-raf oncogenes to transform rat liver epithelial (RLE) cells in vitro. The data indicate that transformation of RLE cells with v-H-ras or v-raf results in increased resistance to the cytotoxins adriamycin, vinblastine and 2-acetylaminofluorene. This multidrug resistance is accompanied by increasing expression of P-glycoprotein (MDR-1) and glutathione-S-transferase P (GST-P). Thus, neoplastic transformation of RLE cells with v-raf or v-H-ras, independently of chemical exposure, results in multidrug resistance.
Carcinogenesis 1988 Dec
PMID:Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals. 290 2

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.
Lab Invest 1988 Dec
PMID:A sensitive method for immunocytochemical detection of P-glycoprotein in multidrug-resistant human ovarian carcinoma cell lines. 290 10

The brown gene of Drosophila melanogaster is required for deposition of pteridine pigments in the compound eye and other tissues. We isolated a ca. 150-kilobase region including brown by microdissection and chromosome walking using cosmids. Among the cDNAs identified by hybridization to the cosmids, one class hybridized to a genomic region that is interrupted in two brown mutants, bw and In(2LR)CK, and to 2.8- and 3.0-kilobase poly(A)+ RNAs which are altered in the mutants. Nucleotide sequencing of these cDNAs revealed that the two transcripts differ as a consequence of alternative poly(A) addition and that both encode the same predicted protein of 675 amino acids. Searches of available databases for amino acid sequence similarities detected a striking overall similarity of this predicted protein to that of the D. melanogaster white gene. The N-terminal portion aligned with the HisP family of membrane-associated ATP-binding proteins, most of which are subunits of active transport complexes in bacteria, and to two regions of the multidrug resistance P-glycoprotein. The C-terminal portion showed a structural similarity to integral membrane components of the same complexes. Taken together with earlier biochemical evidence that brown and white gene products are necessary for uptake of a pteridine precursor and genetic evidence that brown and white proteins interact, our results are consistent with suggestions that these proteins are subunits of a pteridine precursor permease.
Mol Cell Biol 1988 Dec
PMID:The brown protein of Drosophila melanogaster is similar to the white protein and to components of active transport complexes. 314 12

Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P-glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr-1 cells were slightly more sensitive to anti-B4-bR than Namalwa cells; IC37 values were approximately 4 pmol/L and 8 pmol/L, respectively. When anti-B4-bR was combined simultaneously with doxorubicin or etoposide, additive to supra-additive killing of Namalwa and Namalwa/mdr-1 cells was observed. In xenografts of Namalwa/mdr-1 cells in severe combined immunodeficiency (SCID) mice, doxorubicin and etoposide at their maximum tolerated doses (3 mg/kg x 3 or 15 mg/kg x 3) showed no therapeutic effect. However, treatment with 5 daily bolus injections of anti-B4-bR (50 micrograms/kg) followed by treatment with doxorubicin or etoposide significantly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population expressed lower levels of P-glycoprotein, and this decrease may account for the synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with current treatment regimens and further hint at a promising role for this immunotoxin in treatment of disease at the minimal residual disease stage, where cells may be resistant to chemotherapy.
Blood 1995 Dec 01
PMID:Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors. 749 89

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. We have studied here the recently identified transport-associated proteins, MRP and LRP, and the well-known drug resistance marker P-glycoprotein using a panel of 16 human melanoma cell lines and 71 benign and malignant melanocytic tissue samples. By flow cytometry and immunohistochemistry, expression of P-glycoprotein was not detectable on the protein level in the 10 cell lines analyzed, although by reverse transcriptase polymerase chain reaction, MDR-1 gene expression was demonstrated in 2 of 10 cell lines. In addition, immunohistology revealed P-glycoprotein expression in only 1 of 71 melanocytic lesions. In contrast, MRP was detected in a subset of melanoma cell lines by reverse transcriptase polymerase chain reaction and immunohistology (4 of 10). LRP expression was observed in 8 of 10 melanoma cell lines by immunochemistry and in 10 of 10 by reverse transcriptase polymerase chain reaction. Furthermore, MRP was detected immunohistologically in almost 50% of primary and metastatic melanoma specimens, although no significant differences were found between metastases taken before or after chemotherapy. Expression of LRP was detected in a subset of nevi with nevus cells exhibiting up to 25% positive LRP reactivity. In 13 of 21 primary melanomas and 23 of 37 metastases, more than 25% of tumor cells were stained by the LRP-56 monoclonal antibody. Particularly in the group of metastases with more than 50% of LRP-positive cells, 7 of 11 of the metastases had been previously exposed to chemotherapeutic drugs. Although the expression of membrane transport proteins may explain only the chemoresistance toward lipophilic, natural compounds and not resistance against alkylating agents, the lack of P-glycoprotein expression after chemotherapeutic treatment and the significant expression of MRP and LRP in melanoma cells provide first insights into the drug-resistant phenotype in melanoma. Additional studies analyzing the role of MRP and LRP in chemoresistance of melanoma are warranted.
Am J Pathol 1995 Dec
PMID:Membrane transport proteins associated with drug resistance expressed in human melanoma. 749 78


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