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)

This article is a brief review of recent knowledge about the pleiotropic resistant phenotype--multidrug-resistant (MDR) phenotype--which is responsible for cross-resistance in cancer chemotherapy. Thus it is possible to explain chemoresistance to vinca alkaloids, podophyllotoxins and anthracyclines. The MDR phenotype is associated with reduced intracellular drug accumulation by drug efflux, utilizing transmembrane P-glycoprotein (Gp170). The overexpression of Gp170 in normal and cancer tissues and the genetics are reported.
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PMID:Pleiotropic, multidrug-resistant phenotype and P-glycoprotein: a review. 135 45

Feasibility of immunohistochemical staining of P-glycoprotein for the prediction of doxorubicin resistance in gastrointestinal cancers was examined. Among 10 cancer cell lines which consist of two gastric cancer cell lines and eight colon cancer cell lines, seven cell lines were stained positively by the monoclonal antibody to P-glycoprotein, C219. In consequence of the evaluation on the effect of doxorubicin on these tumour cells by means of succinic dehydrogenase inhibition test (SDI test), zero out of seven cell lines stained positively by C219 was sensitive to doxorubicin, but two out of three cell lines stained negatively were sensitive. Among 23 fresh surgical specimens of gastrointestinal cancers which consisted of 15 gastric cancers and eight colon cancers, seven tumour tissues were stained positively by C219. All P-glycoprotein positive tumours were resistant to doxorubicin. On the other hand, four of 16 P-glycoprotein tumours were sensitive to doxorubicin. These data indicate that positively stained cancer cells by C219 are resistant to doxorubicin.
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PMID:Prediction of doxorubicin resistance in gastrointestinal cancer by P-glycoprotein staining. 135 49

Cells displaying the classic multidrug resistant (MDR) phenotype possess a transmembrane protein (p170 or P-glycoprotein) which can actively extrude cytotoxic agents from the cytoplasm. A mathematical model of this drug efflux pump has been developed. Outward transport is modeled as a facilitated diffusion process. Since energy-dependent efflux of cytotoxic agents requires that ATP also bind to p170, the model includes a dynamic calculation for efflux rate which considers Michaelis-Menten kinetics for both the substrate agent and ATP. The final system consists of one partial differential equation (PDE) for the facilitated diffusion of substrate agents out of the cell, a 2 x 2 ordinary differential equation (ODE) system for the dynamic calculation of the ATP-ADP pool, and a dynamic algebraic calculation of the efflux rate given substrate levels at the interior cell membrane interface and ATP levels in the cell. A stability analysis of the ATP-ADP pool distribution and a simplistic closed form solution of the linearized PDE are included. Numerical simulations are also provided.
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PMID:A mathematical model of the P-glycoprotein pump as a mediator of multidrug resistance. 135 83

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.
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PMID:Genetic aspects of multidrug resistance. 135 4

In many cell systems, resistance to cytotoxic drugs is acquired by the amplification and/or overexpression of the multidrug resistance (mdr) gene, which codes for the glycoprotein, p170 (P-glycoprotein). Moreover, in a variety of malignant tumours there is increasing evidence of the relationship between the DNA ploidy pattern of patients and their prognosis. In this study we aimed to evaluate these two potential indicators of constitutive drug resistance in human colorectal tumours. We employed a method to quantify simultaneously, on a per cell basis, mdr gene expression (using the C219 monoclonal antibody for P-glycoprotein) and nuclear DNA content with high-resolution bivariate flow cytometry. The study was performed on a human colon-carcinoma-derived cell line (LoVo) and its doxorubicin-resistant variant (LoVo/Dx) and on tumour samples and adjacent normal mucosa from 35 untreated patients with colon cancer. The P-glycoprotein was found in both LoVo and LoVo/Dx cells with levels slightly lower in the parental than in the resistant subline (P, NS). A multi-drug-resistant specific probe for mRNA expression and Western blot assay confirmed the specificity of p170 expression. All of the colon cancer with unimodal diploid DNA distribution and all the normal colonic mucosa samples showed P-glycoprotein expression, without a statistically significant difference in median values between tumours and normal samples. Tumours with bimodal DNA distribution showed median values of P-glycoprotein expression of their hyperdiploid cell clones significantly higher than those of their diploid clones and of the tumours with unimodal DNA distribution (P less than 0.005). Our results show the feasibility of bivariate flow-cytometric analysis of P-glycoprotein expression and DNA content on clinical material and support the hypothesis that the MDR phenotype and DNA ploidy together may influence the biological behaviour of colon cancer in vivo.
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PMID:Flow cytometric analysis of multidrug-resistance-associated antigen (P-glycoprotein) and DNA ploidy in human colon cancer. 135 83

Expression of multidrug resistance (mdr 1) gene, which encodes a transmembrane efflux pump referred to P-glycoprotein, leads to the decreased intracellular accumulation of various lipophilic drugs, such as vinca alkaloids, anthracyclines and epipodophyllotoxins. As these drugs are commonly used in chemotherapy for acute leukemia, it is of importance to determine whether mdr 1/P-glycoprotein expression is associated with clinical resistance. In several reports, some leukemia cells from untreated patients have expression of mdr 1/P-glycoprotein. We quantitatively detected low levels of mdr 1 expression in all cases of untreated acute leukemia and normal hematopoietic cells, using the reverse transcriptase-polymerase chain reaction. Carefully designed clinical trials including mdr 1 reversing agents may have significant consequences for the treatment of acute leukemia.
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PMID:[Expression of multidrug resistance 1 and correlation with clinical drug resistance in acute leukemia]. 135 71

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.
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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.
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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.
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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.
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PMID:P-glycoprotein expression in locally advanced breast cancer treated by neoadjuvant chemotherapy. 135 61


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