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)

Native resistance to conventional chemotherapy remains an important cause of treatment failure in the adult acute leukemias. Delineation of cellular mechanisms of drug resistance therefore represents a prerequisite to the development of more effective treatment strategies. The multidrug resistance (MDR) phenotype represents one such mechanism of resistance with direct clinical relevance. This phenotype occurs normally in certain mammalian tissues, and is detectable in tumor cell lines selected for resistance to naturally occurring antineoplastics. The mdr1 gene or its glycoprotein product, P-glycoprotein, is detected with high frequency in secondary acute myeloid leukemia (AML) and poor-risk subsets of acute lymphoblastic leukemia. In prospective studies in AML, MDR overexpression is an independent determinant of response to treatment and overall survival with conventional-dose induction regimens. Investigations of mdr1 regulation in normal hematopoietic elements has shown a pattern which corresponds to its regulation in acute leukemia, explaining the linkage of mdr1 to specific cellular phenotypes. Therapeutic trials are now in progress to test the ability of various MDR-reversal agents to restore chemotherapy sensitivity in high-risk acute leukemias.
Leuk Lymphoma 1992 Sep
PMID:Multidrug resistance in acute leukemia: a conserved physiologic function. 128 51

Two new fused indoles were found to overcome multidrug resistance in P388/Adr cells in vitro. These agents potentiated the cytotoxicity of the antitumor drugs Adriamycin, vinblastine, and vincristine in multidrug-resistant cells with no effect on drug-sensitive parent P388 cells. They significantly increased the ATP-dependent accumulation of [3H]-vinblastine and inhibited efflux of the labeled drug from resistant cells. These compounds also inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine in P388/Adr cells and membranes isolated from these cells. In addition, the calcium antagonist activity of these compounds was very weak compared with that of verapamil. These data suggest that the compounds reported here may specifically overcome multidrug resistance without the serious hypotensive effects associated with calcium antagonists and that this activity may be independent of their ability to block calcium transport.
Cancer Res 1992 Sep 01
PMID:Reversal of multidrug resistance by two novel indole derivatives. 135 8

Mammalian cells exposed to a single cytotoxic natural product drug, such as vincristine or dactinomycin, can develop resistance to the selective agent and cross-resistance to a broad spectrum of structurally and functionally distinct antibiotics and alkaloids. This phenomenon, termed multidrug resistance (MDR), has been widely studied experimentally. The most consistent feature of cells with high-level MDR is amplification and overexpression of genes encoding an integral plasma membrane protein known as P-glycoprotein. The MDR genes belong to a small family (two members in humans and three members in mouse and Chinese hamster). Based on several lines of evidence, P-glycoprotein is thought to act as an adenosine triphosphate-dependent efflux pump that decreases accumulation of drugs and increases resistance to their effects. The normal function of P-glycoprotein, apart from its role in MDR, is not known. Proposed roles in detoxification and steroid transport systems are speculative but suggest that the membrane protein may have distinct functions in normal tissues and in tumor cells with acquired MDR. Although possible endogenous substrates for P-glycoprotein have not been identified, insight into normal function may be gained from tissue distribution studies. For example, studies using molecular probes to P-glycoprotein messenger RNA and monoclonal antibodies to different epitopes of the molecule have shown that P-glycoprotein is expressed at high levels in the more differentiated or specialized cells of the colon or kidney. Amplification of MDR genes in vivo has not been observed. Whether intrinsic or acquired MDR plays a causal and potentially modifiable role in clinical nonresponsiveness to cancer chemotherapeutic agents is a topic of current interest. Prospective studies and serial determinations during the course of disease are needed to clarify the importance of this membrane protein in clinical drug resistance.
Cancer 1992 Sep 15
PMID:Genetic aspects of multidrug resistance. 135 4

In an attempt to determine the incidence and clinical relevance of mdr1 gene expression in acute myeloid leukemia (AML), we examined 126 specimens obtained from adult patients with de novo AML by slot blot and immunocytochemistry. We found a high incidence of mdr1 gene expression in newly diagnosed patients (27% by immunocytochemistry and 43% by slot blot). No difference was observed between newly diagnosed patients and relapsed patients. However, patients with resistant disease showed statistically higher incidence of mdr1 gene expression compared to the untreated and relapsing patients (60% versus 27% by immunocytochemistry, p 0.005; and 73% versus 45% by slot blot, p less than 0.05). The expression of mdr1 gene correlated significantly with clinical drug resistance: 62% of patients positive for mdr1-mRNA and 68% of patients positive for P-glycoprotein (P-gp) eventually developed resistance to chemotherapy, while this was the case for a lower percentage of patients who did not express mdr1 gene (only 23% by slot blot analysis, p = 0.0052, or 24% by immunocytochemistry, p = 0.0009). A combined parameter, mdr1-mRNA/P-gp, had a very high prognostic value in terms of specificity and sensitivity. All nine patients (100%) who were mdr1-mRNA+/P-gp+ progressed to clinical drug resistance afterward, whereas 11 of 13 (85%) patients who were mdr1-mRNA-1 P-gp- entered complete remission and only two patients later developed drug resistance (p = 0.0005). It could thus be used as a reliable parameter in clinical settings.
Leukemia 1992 Sep
PMID:Relevance of mdr1 gene expression in acute myeloid leukemia and comparison of different diagnostic methods. 135 75

A 55-year-old woman with chronic myelogenous leukemia developed a lymphoid blast crisis (BC) 10 months after diagnosis. By using immunoblotting with a monoclonal antibody against P-glycoprotein (P-gp) C219, her leukemia cells from the first and 3rd crises were shown to be negative for the P-gp, while the cells of the 4th crisis were detected to have a high level of P-gp. This patient did not respond to chemotherapy with several anti-cancer agents in the 4th crisis, although complete remission was achieved in the first, second and third crises after administration of agents including vincristine and prednisolone. Therefore the expression of P-gp in the 4th BC might have been closely related to the resistance to chemotherapy.
Gan To Kagaku Ryoho 1992 Sep
PMID:[Chronic myelogenous leukemia with blastic crisis in which expression of P-glycoprotein was associated with resistance to chemotherapy]. 135 42

In a variety of adult and childhood leukaemia cell samples collected at different states of the disease, we analysed in a series of sequentially performed slot-blot or Northern-blot hybridisation experiments the expression of genes possibly involved in multiple drug resistance (MDR) (mdr1/P-glycoprotein, DNA topoisomerase II, glutathione-S-transferase pi), and the expression of the DNA topoisomerase I and histone 3.1 genes. Occasionally, P-glycoprotein gene expression was additionally examined by indirect immunocytofluorescence using the monoclonal antibody C219. No significant difference in mdr1/P-glycoprotein mRNA levels between primary and relapsed state acute lymphocytic leukaemias (ALL) was seen on average. Second or third relapses, however, showed a distinct tendency to an elevated expression of this multidrug transporter gene (up to 10-fold) in part well beyond the value seen in the moderately cross-resistant T-lymphoblastoid CCRF-CEM subline CCRF VCR 100. Increased mdr1/P-glycoprotein mRNA levels were also found in relapsed state acute myelogenous leukaemias (AML), and in chronic lymphocytic leukaemias (CLL) treated with chlorambucil and/or prednisone for several years. Topoisomerase I and topoisomerase II mRNA levels were found to be very variable. Whereas in all but one case of CLL topoisomerase II mRNA was not detected by slot-blot hybridizations, strong topoisomerase I and topoisomerase II gene expression levels, frequently exceeding the levels monitored in the CCRF-CEM cell line, were seen in many cell samples of acute leukaemia. If topoisomerase II mRNA was undetectable, expression of topoisomerase I was clearly visible throughout. These observations might be valuable considering the possible treatment with specific topoisomerase I or topoisomerase II inhibitors. Significant positive correlations were found (i) for topoisomerase I and histone 3.1 gene expression levels in general (P less than 0.001), and (ii) in the CLL samples additionally for the expression levels of the mdr1 gene, and the histone 3.1, topoisomerase I, and glutathione-S-transferase pi genes, respectively.
Br J Cancer 1992 Sep
PMID:Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase pi gene expression in primary and relapsed state adult and childhood leukaemias. 135 60

Using immunohistochemistry and the monoclonal antibody C219 we have investigated P-glycoprotein expression in 26 locally advanced breast cancers. Twenty four patients had received four cycles of chemotherapy (mitozantrone, mitomycin-C and methotrexate) prior to mastectomy; two received tamoxifen. Twelve tumours exhibited an objective response to the chemotherapy. A background pattern of isolated weakly positive (1+) stromal staining (myofibroblast) was observed in seven tumours, two of which had been treated by tamoxifen alone. Two of the tumours treated by induction chemotherapy showed positive staining (1+) within a very small number of isolated tumour cells (maximum of three) and macrophages. The significance of this staining is not clear although C219 may simply be cross reacting with myosin. We have failed to demonstrate a clear clinical utility for C219 in breast cancer, particularly regarding the identification of patients in whom MDR chemotherapy be avoided once metastases develop.
Br J Cancer 1992 Sep
PMID:P-glycoprotein expression in locally advanced breast cancer treated by neoadjuvant chemotherapy. 135 61

This study has provided evidence that exposure of the wild-type MCF-7 human breast carcinoma cell line to the mutagen ethyl methane sulphonate (EMS), followed by selection in vincristine (VCR), resulted in a stably-resistant subline, designated VCREMS, which expressed an approximately 14-fold level of resistance to VCR. This VCREMS subline showed cross-resistance (3-fold) to adriamycin (ADR) and to etoposide (3-fold), but not to cisplatin. The addition of a non-toxic concentration of verapamil (6.6 microM) significantly enhanced VCR cytotoxicity only in the resistant subline. This resistance was associated with over-expression of P-glycoprotein (Pgp), but without a concomitant increase in Pgp mRNA or gene amplification. In addition, activities of total glutathione S-transferases (GST) and glutathione peroxidase were elevated in this resistant subline, with over-expression of the GST-pi isozyme and its associated mRNA being identified, without gene amplification. This VCR-selected resistant MCF-7 cell line therefore provides another example of a breast carcinoma subline in which there is co-ordinate over-expression of both Pgp and GST-pi, without attributing a causal relationship to either event, and extends the range of anti-tumour drugs known to elicit modifications in glutathione metabolism.
Int J Cancer 1992 Sep 09
PMID:Over-expression of P-glycoprotein and glutathione S-transferase pi in MCF-7 cells selected for vincristine resistance in vitro. 135 56

Multidrug-resistant human tumor cells overexpress the MDR1 gene product P-glycoprotein, which is believed to function as an ATP-dependent efflux pump. In this study we demonstrate that the partially purified P-glycoprotein, when reconstituted in an artificial membrane, catalyzes drug-stimulated ATP hydrolysis. Plasma membrane proteins of a human multidrug-resistant cell line, KB-V1, were solubilized with 1.4% (wt/vol) octyl beta-D-glucopyranoside in the presence of 0.4% phospholipid and 20% (vol/vol) glycerol, and the crude detergent extract was chromatographed on DEAE-Sepharose CL-6B. The 0.1 M NaCl fraction, enriched in P-glycoprotein but devoid of Na,K-ATPase, was reconstituted by the detergent-dilution method. P-glycoprotein constituted 25-30% of the reconstituted protein in proteoliposomes. ATP hydrolysis by proteoliposomes was stimulated 3.5-fold by the addition of vinblastine but was unaffected by the hydrophobic antitumor agent camptothecin, which is not transported by P-glycoprotein. The stimulatory effect of vinblastine was observed only if the protein was reconstituted in proteoliposomes, suggesting that either the substrate binding site(s) was masked by detergent or that the conformation of the soluble P-glycoprotein might not be suitable for substrate-induced activation. Several other drugs that are known to be transported by P-glycoprotein enhanced the ATPase activity in a dose-dependent manner with relative potencies as follows: doxorubicin = vinblastine greater than daunomycin greater than actinomycin D greater than verapamil greater than colchicine. The basal and vinblastine-stimulated ATPase activities were inhibited by vanadate (50% inhibition observed at 7-10 microM) but were not affected by agents that inhibit other ATPases and phosphatases. These data indicate that the P-glycoprotein, similar to other ion-transporting ATPases, exhibits a high level of ATP hydrolysis (5-12 mumol per min per mg of protein).
Proc Natl Acad Sci U S A 1992 Sep 15
PMID:Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. 135 64

Presentation of doxorubicin in liposomes has shown to enhance the sensitivity of multidrug resistant CH LZ cells to the drug (Thierry et al. Cancer Commun. 1:311-316, 1989). We confirmed that liposomally encapsulated doxorubicin may partially overcome multidrug resistance in the human ovarian carcinoma SKVLB cell line and that this effect is, at least in part, due to an increase of cellular drug accumulation. When used at high concentration, empty liposomes appear to be specifically cytotoxic in the MDR SKVLB and CH LZ cells. As observed with certain multidrug resistance modulators, empty liposomes inhibited the specific [3H]-vincristine binding to P-glycoprotein-enriched membranes isolated from CH LZ cells (60% at 0.2 mg lipid/ml). Our data suggest that liposomes may alter the P-glycoprotein function by direct interaction.
Biochem Biophys Res Commun 1992 Sep 16
PMID:Effect of liposomes on P-glycoprotein function in multidrug resistant cells. 135 35


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