Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein plays a key role in multidrug resistance of tumor cells. In order to elucidate the possible quarternary structure/function relationship of P-glycoprotein, we treated multidrug-resistant human leukemia K562/ADM cells with the crosslinking reagent, disuccinimidyl suberate. In addition to 180K P-glycoprotein, a 340K protein was immunoprecipitated with an anti-P-glycoprotein monoclonal antibody, MRK-16. The 340K protein is most probably a dimeric P-glycoprotein, since only the 180K P-glycoprotein was immunoprecipitated with MRK-16 when K562/ADM cells were treated with the cleavable crosslinking reagent, dithiobis(succinimidylpropionate), and analysed under reduced conditions. The dimeric P-glycoprotein was photolabeled with [3H]azidopine like the 180K monomeric P-glycoprotein and the photolabeling was inhibited by excess amount of vincristine and verapamil. The dimeric P-glycoprotein could be a functionally active form of the protein involved in the transport of antitumor agents.
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PMID:Functionally active homodimer of P-glycoprotein in multidrug-resistant tumor cells. 135 Sep 3

An 85-kDa protein was identified in adriamycin-resistant tumor cells recognized by monoclonal antibody MRK-20. Recently, the monoclonal antibody MRK-20 was found to be reactive to human peripheral mononuclear cells. In order to investigate the molecular function of the 85-kDa protein, we carried out flow cytometric analysis of the expression of the 85-kDa protein during monocytic differentiation of the hematopoietic cells. Human myelomonocytic leukemia THP-1 cells were induced to differentiate into macrophage-like cells by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). A maximum of 55% of the cells expressed the 85-kDa protein along with the CD-14 antigen, which is a surface marker of monocytes and macrophages. The kinetic analysis revealed that the 85-kDa protein appeared prior to the expression of the CD-14 antigen. The 85-kDa protein was also coexpressed with CD-14 in THP-1 cells that were induced to differentiate by recombinant tumor necrosis factor-alpha, which is one of the physiological inducers of monocytic differentiation. In human erythroleukemia, HEL cells, the 85-kDa protein was constitutively coexpressed with CD-14. The expression of both the 85-kDa protein and CD-14 was drastically reduced during the megakaryocytic differentiation of the HEL cells with TPA. These results suggest that the 85-kDa protein could be expressed on monocytic cells as well as CD-14 and that the expression of the 85-kDa protein might be regulated at an earlier stage of monocytic differentiation of hematopoietic cells than the expression of CD-14.
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PMID:Expression of 85-kDa protein of adriamycin-resistant tumor cells during hematopoietic differentiation of THP-1 and HEL cells. 137 89

Flow cytometric detection of surface P-glycoprotein, a multidrug-resistant gene product, with a monoclonal antibody, MRK 16, was performed on cells obtained from 18 children with leukaemia and lymphoma. Of 18 patients examined, 1 with malignant lymphoma at relapse showed a significant increase in P-glycoprotein-positive cells and a strong resistance to chemotherapy. Overexpression of P-glycoprotein in a case with B-cell type malignant lymphoma was confirmed by immuno-precipitation and Northern hybridization analysis. The present study suggests that an increased expression of surface P-glycoprotein might be involved in multidrug resistance at least in a certain case of childhood leukaemia and lymphoma.
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PMID:Detection of multidrug-resistant protein, P-glycoprotein in childhood leukaemia and lymphoma. 167 13

The ability of cyclosporin to modify drug accumulation in vitro, measured by the cellular accumulation of daunorubicin, was examined. In 42 patients with chronic lymphatic leukaemia this correlates well with the levels of P-glycoprotein (Pgp) measured by immunofluorescent labelling of Pgp after treatment of the cells with neuraminidase to unmask the epitope recognized by the monoclonal antibody MRK 16. It is shown that flow cytometric analysis using MRK 16 to detect Pgp expression levels together with drug accumulation studies can rapidly assess the multidrug-resistant phenotype of patients' cells, and enable selection of those suitable for therapy with agents known to circumvent mdr-1 mediated drug resistance.
Leukemia 1991 Dec
PMID:Increased drug accumulation ex vivo with cyclosporin in chronic lymphatic leukemia and its relationship to epitope masking of P-glycoprotein. 168 51

Resistance to cytotoxic agents is a common clinical problem in the treatment of chronic lymphatic leukaemia (CLL). The multidrug resistant (MDR) phenotype characterized by increased levels of a specific cell membrane p-glycoprotein, confers cross resistance to a wide range of structurally dissimilar antineoplastic drugs. We have studied the expression of this p-glycoprotein in chronic lymphatic leukaemia measured by immunofluorescence using a monoclonal antibody MRK 16 by flow cytometry. Initial results showed that only 12% of lymphocyte samples from CLL patients showed increased p-glycoprotein, conflicting with a previous observation that 53% of CLL patients had an increased level of mdr-1 mRNA. Treatment of the cells with neuraminidase to remove sialic acid residues increased the proportion of patients showing increased p-glycoprotein to 52%. This suggest that in a subset of CLL patients post translational modification of the protein occurs masking the epitope recognized by MRK 16. Abnormal sialylation patterns associated with malignancy are a well-recognized phenomenon.
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PMID:Expression of the multiple drug resistance gene (mdr-1) and epitope masking in chronic lymphatic leukaemia. 170 6

This paper describes the cellular and tissue distribution of P-glycoprotein (P-GP) (mdr1 gene product), the role of P-GP in vivo and immunodiagnosis of multi-drug-resistant cancers. We mainly used MRK 16 monoclonal antibody (MAb) reactive with P-GP. P-GP was found to be expressed very strongly in the adrenal cortex of adults and strongly in the renal tubules of the kidney, capillary blood vessels of the brain, and also in placenta. Interestingly, P-GP was not distributed in fetal and neonatal adrenals, and thus may be closely related to adrenal maturation. A high level of P-GP expression was also seen in all cases of functional hormone-producing adrenal tumor, one case of insulinoma, two cases of untreated colonic cancer, one case each of untreated lung cancer, gastric cancer and breast cancer, six cases of renal cell carcinoma and 17 cases of bladder cancer. Using flow cytometry and immunocytochemistry, we investigated the reactivity of MRK 16 MAb with peripheral human mononuclear cells (mainly blastic cells and lymphocytes) from 31 patients with leukemia or malignant lymphoma. Reactivity with MRK 16 MAb was observed in five cases. Some cases reflected the prior administration of adriamycin, vincristine and VP-16, which are known to induce P-GP expression. P-GP-MRK 16-protein A-Sepharose complex derived from human adrenal possessed marked ATPase activity. These data suggest that P-GP may play a physiological role in the human adrenal. Finally, diagnostic criteria of multi-drug-resistant cancers are presented.
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PMID:Expression and functions of P-glycoprotein (mdr1 gene product) in normal and malignant tissues. 197 61

Two monoclonal antibodies of F (ab')2 form, MRK 16 and MRK 20 that recognize P-glycoprotein and P85 kD protein respectively, were useful to detect multidrug resistant cells in human lymphoma, leukemia and gastrointestinal cancer cell lines. They were classified into 4 groups: Group I (4 cell lines) was insensitive to vinca alkaloids, anthracyclines, etoposide (VP-16) and actinomycin-D (ACT-D), and reactive to MRK 16 and MRL 20. Group II (2 cell lines) was insensitive to vincristine (VCR), but not reactive to both antibodies. Group III (3 cell lines) was insensitive to anthracyclines and VP-16, but sensitive to vinca alkaloids and ACT-D, and reactive to MRK 20 but not to MRK 16. Group IV (all other cell lines) was sensitive to these drugs, and not reactive to both antibodies. MRK 16 detects P-glycoprotein-associated multidrug resistance (MDR), while MRK 20 detects P 85kd-associated novel MDR. These monoclonal antibodies were useful for detection of MDR cells in clinical samples.
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PMID:[Detection of multidrug resistant cells in human malignant diseases by monoclonal antibodies and strategy to eradicate resistant malignant cells]. 256 3

Using flow cytometry and immunocytochemistry, we investigated the reactivities of two different murine monoclonal antibodies (MAbs), MRK 16 and MRK 20, specific to adriamycin-resistant K562 cells (K562/ADM) with peripheral human mononuclear cells (MNC) (mainly blastic cells and lymphocytes) from 31 patients with leukaemia or malignant lymphoma. Reactivity with MRK 16 MAb was observed in five cases and reactivity with MRK 20 MAb in 18 cases. The cases were divided into three groups according to their reactivity patterns: group I, only the proportion of MRK 16-positive cells was increased; group II, only the proportion of MRK 20-positive cells was increased; group III, both MRK 16-and MRK 20-positive cells were increased. Some cases reflected the prior administration of adriamycin, vincristine, vinblastine and VP-16, which are known to induce P-glycoprotein expression. Expression of Mr 85,000 protein was observed more frequently than that of P-glycoprotein in leukaemia and malignant lymphoma, and this was not associated with either the total dose or period of administration of anticancer drugs. The expression of Mr 85,000 protein recognised by MRK 20 was further confirmed by Western blot analysis.
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PMID:High-level expression of MRK 16 and MRK 20 murine monoclonal antibody-define proteins (170,000-180,000 P-glycoprotein and 85,000 protein) in leukaemias and malignant lymphomas. 257 70

The effectiveness of ex vivo chemotherapy with drugs, such as vincristine, etoposide, and Adriamycin (doxorubicin, Adria Labs, Columbus, OH) for elimination of residual tumor cells from human bone marrow grafts could be undermined by the presence of multidrug-resistant tumor cells in the bone marrow. Therefore, to supplement chemoseparation, we investigated whether MRK-16, a monoclonal antibody (MoAb) to the surface moiety of multidrug resistance-associated P-glycoprotein antigen, can eliminate drug-resistant tumor cells in the presence of rabbit complement (RC). Two doxorubicin (DOX)-resistant human myeloma tumor cell line, 8226/DOX40 (resistant to 4 x 10(-7) mol/L DOX) and 8226/DOX6 (6 x 10(-8) mol/L DOX) with high and low amounts of cell surface P-glycoprotein, respectively, and the drug-sensitive parent cell line 8226/S were used as tumor models in this study. Using the limiting dilution assay, we have shown that three cycles of treatment with 25 micrograms/mL of MRK-16 MoAb and a 1:4 final dilution of RC eliminated 2.90 +/- 0.10 logs of 8226/DOX40 cells and 1.94 +/- 0.18 logs of 8226/DOX6 cells. One and two cycles of treatment were less effective, eliminating 0.47 +/- 0.40 and 1.94 +/- 0.36 logs of 8226/DOX40 and 0.12 +/- 0.20 and 1.63 +/- 0.58 logs of 8226/DOX6 cells, respectively. The 8226/S cell growth was unaffected by one to three cycles of treatment. The cell kill was not impaired when the antibody plus complement treatment was carried out on a mixture of 8226/DOX40 or 8226/DOX6 cells with a ninefold excess of irradiated bone marrow mononuclear cells (MNCs). The three cycles of treatment with antibody plus complement did not adversely affect granulocyte-macrophage colony-forming unit (GM-CFU) survival in hematologically normal marrows (92.5% to 104% survival) or in myeloma patient marrows (85% to 100%). These results show that it is possible to eliminate drug-resistant myeloma tumor cell lines from the admixed human bone marrow by treatment with MRK-16 MoAb plus RC. This method could prove to be effective for elimination of other drug-resistant tumor cell lines including those of leukemia and solid tumors, and will be further useful for supplementing chemopurging, and immunopurging of bone marrow with other antitumor cell antibodies.
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PMID:Elimination of drug-resistant myeloma tumor cell lines by monoclonal anti-P-glycoprotein antibody and rabbit complement. 257 83

Expression of the multidrug resistance efflux pump P-glycoprotein (Pgp) was measured in a series of AML patients using two flow cytometry methods. Transport function was assessed by measuring the modulating effect of the Pgp inhibitor cyclosporin A (CsA) on the cellular accumulation of daunorubicin, and Pgp antigen expression by surface immunofluorescence using the MRK-16 antibody. Both methods showed a wide range of values for Pgp expression between individual patients, but in contrast to a series of cell lines expressing Pgp there was no correlation between antigen expression and transport function in the clinical samples. As previously reported for chronic lymphocytic leukemia (CLL), pretreatment with neuraminidase markedly improved MRK-16 staining in some cases, indicating that abnormal glycosylation can cause epitope masking in AML blasts. Because experience with cell lines shows that Pgp expression is a continuous variable which correlates with the level of drug resistance, rather than the 'positive' or 'negative' which are frequently reported by clinical flow cytometry laboratories, we used a calibration procedure to estimate the actual number of Pgp molecules expressed in the AML samples. Despite the additional refinements of neuraminidase treatment and antigen quantification, the correlation between Pgp antigen expression and daunorubicin accumulation remained extremely weak (r = 0.11; P = 0.63). It is suggested that the assay for transport function can detect molecules that affect daunorubicin accumulation but are antigenically distinct from classical P-glycoprotein. Heterogeneity of multidrug resistance efflux pumps might in part explain the relatively weak prognostic significance of immunofluorescence detection of Pgp in AML patients.
Leukemia 1995 Nov
PMID:Discordant P-glycoprotein antigen expression and transport function in acute myeloid leukemia. 747 79


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