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)

Multidrug resistance (MDR) is associated with expression of P-glycoprotein in the malignant cells as the one of known mechanisms for this phenomenon. The isolated blast cells of 60 patients with acute leukemia and non-Hodgkin's lymphoma (NHL) were assayed for the expression of P-glycoprotein (P-170) with MRK16 antibody. The frequency of P-170 expression was studied in the different subtypes of leukemia and NHL based on blasts phenotype. In acute leukemia and lymphoma with B cell lineage of blast cells the percentage of P-170 positive samples was 41.3%, in the non-lymphoblastic leukemia--35.3% and the T cell lineage--75% of P-170 positive samples. The expression of P-170 molecule was associated with: 1. T cell origin of blasts, 2. lymphoma form of proliferation. The P-170 assay selects the group of patients with higher risk of drug resistance for modified therapy.
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PMID:The expression of multidrug resistance (MDR) molecule in acute leukemia and lymphoma. 764 Sep 50

MDR1 gene expression was examined in acute leukemia cells from 75 Japanese patients at diagnosis (50 with acute myeloblastic leukemia [AML]: 10 M1, 18 M2, 5 M3, 8 M4, 9 M5; 25 with acute lymphoblastic leukemia [ALL]: 13 B-precursor, 12 T-lineage). The results of MDR1 mRNA expression by reverse transcriptase polymerase chain reaction were confirmed by immunostaining using the anti-P-glycoprotein monoclonal antibody UIC2 and by a functional study using the rhodamine efflux test. Morphologically, AML M1 cases had the highest incidence of MDR1 gene expression (6 of 10 patients). Phenotypically, CD7 and CD34 were the only surface markers that were significantly associated with MDR1 gene expression (P < .01). In CD7+CD4-CD8- ALL, which is thought to originate from the lymphohematopoietic stem cell, expressed the MDR1 gene with a high incidence (six of eight patients), whereas three surface CD3+ and one CD4+CD8+ T-cell ALL (T-ALL) did not have detectable MDR1 transcripts. Only two cases of 13 B-precursor ALL had MDR1 mRNA, one of which had the Philadelphia (Ph1) chromosome. No association was observed between MDR1 gene expression and CD34 positivity in ALL. Our results that MDR1 mRNA was frequently expressed in CD7+ AML and CD7+CD4-CD8- ALL, together with the previous reports indicating clinical similarities between these leukemias, provides a clue to clarify a relationship between CD7+ AML and CD7+CD4-CD8- ALL. In addition, MDR1 expression in CD7+ AML/ALL might be responsible for the poor response to conventional chemotherapies of these types of leukemia.
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PMID:Expression of MDR1 gene in acute leukemia cells: association with CD7+ acute myeloblastic leukemia/acute lymphoblastic leukemia. 769 87

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.
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PMID:Patterns of drug resistance parameters in adult leukemia. 777 47

Bone marrow specimens from 100 cases of acute leukemia (AL) diagnosed by MIC were detected with fluorescence microscopy for their mdr-1 expression using monoclonal antibody JSB-1 against P-glycoprotein (P-170). The results showed that almost all subtypes of AL had P-170 expression and M5 of ANLL had a significantly higher expression rate in the newly diagnosed group. The MDR expression highly correlated with the clinical drug resistance and prognosis. The Positive rate of P-170 (20.8% +/- 14.9%) and MDR expression (78.9%) of refractory group were significantly higher than newly diagnosed group (7.5% +/- 9.8% and 18.2% respectively). Cases with MDR expression had poor response to chemotherapy and bad prognosis.
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PMID:[Detection and analysis of multidrug resistance in 100 cases of acute leukemia]. 789 88

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90-96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2R beta and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCR delta and TCR beta, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearrangement of one allele for both JH and TCR beta but no HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-alpha, MIP-1 alpha, IL-10 and interferon gamma and modest amounts of IL-1 alpha, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented a leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.
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PMID:Phenotype, genotype and cytokine production in acute leukemia involving progenitors of dendritic Langerhans' cells. 791 55

Ether phospholipids are new anti-neoplastic drugs that have been found active against a variety of tumor cell lines, including drug-resistant sublines. We have characterized the antiproliferative activity of three ether phospholipids, i.e. ET-18-OCH3 (Edelfosine), BM 41.440 (limofosine) and a new aza-derivative (BN 52205), on three leukemic cell lines, i.e. K562 (chronic myeloid leukemia, blast crisis), HL60 (promyelocytic acute leukemia) and CEM (T cell leukemia), and their respective drug-resistant sublines, i.e. K562-ADR (adryamicin resistant), HL60-DNR [daunorubicin (DNR) resistant] and CEM-VLB (vinblastin resistant). These resistant sublines have been found to express the multidrug-resistant phenotype, revealed by the presence of the P-glycoprotein (PgP) using different monoclonal antibodies. Increased cellular accumulation of the fluorescent anthracycline has been found in both sensitive and resistant cell lines after different ether phospholipid treatment times. In resistant cells, the ether phospholipid effect on DNR accumulation has also been found after blocking the PgP function by verapamil and cyclosporin A. These results confirm that the ether phospholipid action is closely linked with the membrane biochemical composition and that these new anti-tumor drugs are able to change the dynamic structural organization of the tumor cell membrane.
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PMID:Flow cytometric monitoring of anthracycline accumulation after anti-neoplastic ether phospholipid treatment. 791 58

Expression of the multidrug-resistant (MDR) phenotype was investigated in acute leukemia using a monoclonal antibody (HYB-241) directed against a cell surface epitope of the 180 kd P-glycoprotein (gp180) by flow cytometric analysis of clinical samples. Samples from sixty-four patients were tested (37 with acute myelocytic leukemia, 20 with acute lymphocytic leukemia, and 7 with blastic chronic myelocytic leukemia). A D value (derived from Kolmogorov-Smirnov test) greater than 0.15 was considered positive (+). Eight of 32 newly diagnosed patients were positive for gp180 compared with 22 of 32 relapsed/refractory (R/R) patients (P < 0.001). Of the new patients, vinca/anthracycline-based induction therapy failed in 3/6 gp180(+) and 5/18 gp180(-) patients. In the R/R group, 15/16 gp180(+) and 3/6 gp180(-) patients failed to achieve complete remission (P < 0.05). In vitro drug accumulation studies performed with verapamil failed to show a correlation with clinical response. However, in a subset of patients, a striking correlation (r = .97, P = .001) was noted between the presence of gp180 as determined by the D value and the functional activity of the P-glycoprotein as expressed by increased daunorubicin accumulation in the presence of verapamil. The results suggest that 1) newly diagnosed patients can express gp180, 2) P-glycoprotein is expressed in 69% of R/R patients, 3) response in R/R patients is effected by the presence of gp180, and 4) expression of gp180 is highly correlated with its function as a drug-efflux pump in a subset of the patients studied. The complexity of clinical drug resistance is underscored by the finding that the MDR model is not applicable to all cases. In such instances, other mechanisms may play a predominant role.
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PMID:Flow cytometric determination of the multidrug-resistant phenotype in acute leukemia. 800 61

HL-60-R, a multi-drug-resistant (MDR) subclone of the human leukemia cell line HL-60, was selected in continuous culture in doxorubicin (DOX) in the absence of mutagenic agents. When compared to the parent line HL-60, HL-60-R showed greater relative resistance to vinblastine than to etoposide, or to the selecting agent DOX. Co-exposure to verapamil, a known modulator of MDR, partially increased its sensitivity to DOX and vinblastine. The HL-60-R cell line stained positively with the P-glycoprotein-specific monoclonal antibody (MAb), C219, whereas the HL-60 parent was negative. Southern analysis showed 32-fold amplification of the mdrI gene in HL-60-R, whereas slot-blot analysis demonstrated 70-fold over-expression of the specific mdrI message in HL-60-R compared to HL-60. Northern blot analysis revealed the presence of 2 species of messenger RNA of sizes 5.1 kb and 4.5 kb. No transcripts were detectable in the parent. Flow cytometric analysis showed significantly reduced cellular retention of DOX as well as rapid efflux from the drug-resistant cell line. HL-60-R proved to be nearly 4 times more resistant to hydrogen peroxide than its parent, and 1,000 times more resistant to inhibition of cellular glutathione synthesis by D,L-buthionine sulfoximine (BSO). Verapamil modulated DOX resistance in HL-60-R incompletely but, in the presence of glutathione depletion, nearly completely reversed DOX resistance. Elevated levels of glutathione and glutathione-peroxidase activity were demonstrated, thereby implicating enhanced activity of the glutathione/glutathione-peroxidase cycle as an additional basis for its resistance to DOX. These findings suggest that an enhanced capacity for detoxifying oxyradicals may contribute to anthracycline resistance in acute leukemia.
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PMID:P-glycoprotein and alterations in the glutathione/glutathione-peroxidase cycle underlie doxorubicin resistance in HL-60-R, a subclone of the HL-60 human leukemia cell line. 809 91

The curative potential of chemotherapy for a number of tumor types has been obscured by the fact that many patients initially have striking remissions but later relapse and die. At the time of relapse many patients manifest resistance to a wide array of structurally unrelated antineoplastic agents, hence the term multidrug resistance (MDR). Other tumor types, such as those arising in the colon, kidneys, liver, and lungs, tend to exhibit poor response to available cytotoxic drugs. The MDR phenomenon includes cross-resistance among the anthracyclines (doxorubicin, daunorubicin), the epipodophyllotoxins (etoposide, teniposide), the vinca alkaloids (vinblastine, vincristine), taxol, and other compounds. In vitro studies in cell culture indicate that this form of resistance is associated with amplification or overexpression of the mdr1 gene. The mdr1 gene codes for the expression of a cell surface protein, P-glycoprotein (P-gp), which acts as an energy-dependent efflux pump that transports drugs associated with MDR out of the cell before cytotoxic effects occur. The protein is expressed in normal human tissues such as the gastrointestinal tract, liver, and kidneys, where it is thought to serve as an excretory pathway for xenobiotic drugs and toxins. Preliminary studies demonstrated the presence of P-gp in tumor samples from patients with acute leukemia, multiple myeloma, lymphomas, and a variety of solid tumors. A number of drugs are able to reverse MDR, including calcium-channel blockers, phenothiazines, quinidine, antimalarial agents, antiestrogenic and other steroids, and cyclosporine. Limited results from clinical trials with small numbers of patients suggest that the addition of verapamil, diltiazem, quinine, trifluoperazine, or cyclosporine to chemotherapeutic regimens has the potential to reverse MDR; however, toxicities limit their clinical usefulness. A number of trials are under way to identify more active and less toxic modulators of MDR.
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PMID:Molecular targets in oncology: implications of the multidrug resistance gene. 809 38

The phenomenon of multidrug resistance (MDR) is frequently encountered in clinical situations, and could contribute to the failure of chemotherapy in acute leukemia. Preliminary studies have suggested that MDR1 gene expression in normal hematopoietic stem cells might be downregulated during differentiation. In the present study, we induced a multidrug-resistant promyelocytic leukemia cell line, HL60/DNR, to myeloid differentiation by exposure to all-trans retinoid acid and dimethyl sulfoxide (DMSO). We found that HL60/DNR cells retained the ability to respond to the differentiation stimulus. However, although MTT assays revealed a slight decrease of IC50 in differentiated cells, neither efflux of daunorubicin (DNR), nor expression of P-glycoprotein (P-gp), nor quantity of MDR1 mRNA has been downregulated in differentiated cells. We can conclude, therefore, that MDR1 gene expression in this multidrug-resistant myeloid cell line is not modified by induction of its differentiation.
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PMID:Effect of differentiating agents on modulation of MDR1 gene expression in multidrug-resistant hematopoietic HL60/DNR cell line. 809 18


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