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 series of MDR cell lines with various levels of P-glycoprotein have been established from a human colorectal carcinoma cell line, HCT-15, by stepwise exposure to adriamycin. The relative drug resistance of these cell lines correlated directly with both MDR1 mRNA levels and P-glycoprotein expression levels. Intracellular accumulation of adriamycin decreased inversely to their resistance. Drug sensitivities of these lines were reversed using verapamil. Since these cell lines are transplantable to nude mice, they may provide a useful animal model of MDR solid tumors for therapeutic experiments.
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PMID:Establishment of multidrug resistant human colorectal carcinoma HCT-15 cell lines and their properties. 167 19

Immunohistological detection of P-glycoprotein (P-gp) with monoclonal antibody C219 was performed on serial sections of 37 neuroblastoma specimens representative of the different forms of the disease, from stage 1 ganglioneuroma to stage 4 neuroblastoma. Malignant cells, irrespective of their degree of maturation varying from neuroblasts to ganglion cells, were negative on all specimens. The expression of P-glycoprotein was detected in nine specimens, but it was restricted to normal cells within the tumour. In four specimens, C219 reacted with normal infiltrating cells in the stroma (i.e. monocytes, histiocytes or fibroblasts) representing 5 to 10% of the total population within the section; in three specimens, the residual adrenal gland was strongly positive, and in two ganglioneuromas, a weak reactivity of C219 was observed on a few satellite cells and schwann cells. Three of 15 biopsies obtained at diagnosis contained normal P-gp positive cells: two were classified as stage 1 ganglioneuromas; one was a typical stage 4 composite tumours with positive histiocytes and fibroblasts in the well-differentiated counterpart. Six of 22 biopsies obtained after patients had received our current protocol of chemotherapy contained normal P-gp positive cells: five were partially differentiated and necrotic under the effect of chemotherapy; only one positive specimen was classified as undifferentiated neuroblastoma. Among negative specimens from previously treated patients, one was obtained from a patient in relapse after high-dose chemotherapy and ABMT, two were obtained from patients who had not responded to induction therapy, and six from patients in partial remission after induction therapy. The clinical evolution was very similar in both groups of patients with P-gp negative or positive biopsies. These findings suggest that the quantitative assessment of MDR RNA by northern blotting on fresh homogenates is likely to overestimate its expression on neuroblastoma cells, and that the mechanism of chemoresistance in widespread neuroblastoma is less likely to be associated with P-gp expression.
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PMID:Expression of P-glycoprotein restricted to normal cells in neuroblastoma biopsies. 167 95

We detail our experience with a monoclonal antibody to detect the cell surface P-glycoprotein product of the multidrug resistance gene (MDR-1) in the human bladder. A total of 32 patients had 44 different specimens analyzed. The samples consisted of 8 normal bladders, 21 transitional cell carcinomas, 1 mucinous adenocarcinoma, 3 P-0 bladder wall specimens and 10 nonmalignant urothelial samples from cystectomies. P-glycoprotein was not detected in the normal adult or pediatric bladder. Bladder specimens from 3 children with a neurogenic bladder revealed enhanced expression (21%, 14% and 4% positivity). Transitional cell carcinoma usually demonstrates low expression at diagnosis (less than 6%), although 3 patients had enhanced initial expression (11%, 12% and 31%). Three patients treated with chemotherapy demonstrated 56%, 76% and 50% expression of MDR-1. Nonmalignant tissue from cystectomy specimens had low expression of MDR-1. The specificity of this system was confirmed with human bladder cell lines. The ability of flow cytometry to detect and quantify the expression of MDR-1 may allow for the early detection of chemotherapy resistance in patients with transitional cell carcinoma treated with systemic and intravesical therapy.
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PMID:Flow cytometric determination of the multidrug resistant phenotype in transitional cell cancer of the bladder: implications and applications. 168 Feb 3

The development of resistance to chemotherapy is a major problem in the treatment of malignant tumors. Clinically, this is characterized by short periods of remission and failure to respond to subsequent therapy. Multidrug-resistance or pleiotropic resistance describes the simultaneous expression of cellular resistance to a vide range of structurally unrelated drugs (e.g. alkaloids, anthracyclines, antibiotics, etc.). The most frequently reported alteration of multidrug-resistant cells is the overexpression of a 170 kD glycoprotein (P--170 or P-glycoprotein) encoding by the MDR gene family. A great deal of evidence has suggested that the P-glycoprotein is, in fact, an energy-dependent drug efflux pump. Pharmacological overcome of MDR may indicate to circumvent clinically observed drug resistance.
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PMID:[Multidrug resistance of malignant tumors]. 168 63

The molecular genetic characterization of MDR human, mouse, and hamster P-glycoprotein genes has identified several elements that may contribute to the diversity in multidrug-resistance phenotype associated with P-glycoprotein expression. First, spontaneous mutations within the MDR genes may alter the relative affinity of P-glycoprotein for certain drugs or alter the substrate specificity of the protein. Secondly, alternative splicing of MDR mRNA may result in isoforms with different substrate recognition or transport properties. Differential splicing has not thus far been demonstrated for human MDR1 or mouse mdr1a and mdr1b genes. Finally, differential expression of mdr genes encoding P-glycoprotein isoforms with distinct properties appears to be a possible mechanism for generating diversity in MDR rodent cells.
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PMID:Molecular biology of P-glycoprotein. 168 22

We report a case of ectopic salivary amylase-producing IgA- lambda-type multiple myeloma. A 70-year-old man was admitted because of anemia and renal failure. After chemotherapy for eight months, the serum amylase markedly increased. Amylase activity in the supernatant of cultured myeloma cells, which were obtained from the bone marrow, also increased. The myeloma cells expressed MDR-1/P-glycoprotein). The case implies the association of drug resistance and the ectopic amylase production in a case of multiple myeloma.
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PMID:[Ectopic salivary amylase-producing IgA- lambda-type multiple myeloma with expression of MDR-1/P-glycoprotein]. 171 26

We investigated the chemosensitisation of the parental EMT6 mouse mammary tumour cell line by low doses of cyclosporin A (CsA). This cell line has not previously been exposed to cytotoxic drugs but expresses low levels of P-glycoprotein. We produced greater than 2-fold sensitisation to doxorubicin, colchicine and vincristine using 0.084 microM (0.1 micrograms/ml) CsA. Cellular accumulation of doxorubicin and daunorubicin was also increased by this dose. In the MDR subline EMT6/AR1.0, much higher doses of CsA were required to effect optimal restoration of doxorubicin or daunorubicin accumulation. The effects of CsA on the parent line could not be increased by extended preincubation of cells with the sensitiser. These effects of CsA in the EMT6 parent cell line occur at a dose that is 1 order of magnitude lower than those previously reported to produce significant chemosensitisation.
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PMID:Chemosensitisation of a drug-sensitive parental cell line by low-dose cyclosporin A. 174 45

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.
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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.
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PMID:Expression of a multidrug resistance gene in esophageal adenocarcinoma. Correlation with response to chemotherapy and comparison with gastric adenocarcinoma. 239 10

Agents capable of reversing multidrug resistance (mdr) in falciparum malaria were investigated for potentiation of chloroquine accumulation and toxicity in a cell culture system. Verapamil, its analog RO11-2933, and desipramine caused a dose-dependent increase in the accumulation of chloroquine (CQ) within human and mouse hepatocytes but not human lung cells. Only those cells in which drug accumulation was enhanced by reversing agents reacted positively for P-glycoprotein (PgP)--the putative mediator of the enhanced drug efflux characteristic of mdr. Clinically achievable concentrations of verapamil (0.4 microM) and desipramine (1 microM) increased CQ accumulation within primary mouse hepatocytes by more than 50%. A well-differentiated normal human cell line (Hep-G2) was killed in media containing a combination of supraphysiological concentrations of CQ and verapamil but survived the same concentrations of either drug alone. Reversing agents may block PgP-mediated drug export from normal tissues as well as from MDR cells. Iatrogenic toxicity resulting from this accumulation of potentially toxic drugs such as CQ within normal cells could complicate the reversal of mdr in vivo.
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PMID:Reversal of drug-resistant falciparum malaria by calcium antagonists: potential for host cell toxicity. 197 36


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