Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toremifene, apart from its partial estrogen antagonism, exerts multiple and varied effects on a variety of genes involved in the control of signalling and apoptosis. After three weeks of exposure of R3230AC hosting rats to therapeutical oral doses of toremifene distinct changes in steroid receptors, P-glycoprotein, p53 and Bc1-2 expression and protein S100 levels occurred, which may contribute to our understanding of the mechanisms of action of this antiestrogen.
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PMID:The effect of toremifene on the expression of genes in a rat mammary adenocarcinoma. 889 31

CD44 variants carrying sequences encoded by exon v6 are preferentially expressed in metastatic animal cancer cell lines. CD44v6 overexpression correlates tumor dedifferentiation and progression in some human carcinomas, but the relationship of CD44v6 overexpression with metastatic behavior of tumor observed in animal models is controversial, particularly in breast carcinomas. The discrepancies probably result from analytical bias. We investigated CD44v6 and CD44s expression in 218 frozen samples of primary breast carcinomas. Immunocytochemical procedure was performed under optimal technical conditions using commercially available 2F-10 monoclonal antibody (MAb), a microprocessor-controlled automated device (Ventana Medical Systems, Tucson, AZ), and quantitative evaluation of results by processing digitized-colored microscopic images (SAMBA, Grenoble, France). CD44v6 expression in tissue sections was shown to be independent of the patient age, tumor size, histological types and grades, and the lymph node status. CD44v6 expression was also independent of the expression of molecules endowed with poor prognostic significance detected by MAbs (anti-p53, anti-c-erb B-2 protein, MIB1) on consecutive sections. No significant relationship could be evidenced either between CD44v6 expression, and CD31 involved stromal angiogenesis and cathepsin D. Finally, CD44v6 was independent of markers of hormone dependence (estrogen and progesterone receptors, pS2) and of multidrug resistance (P-glycoprotein). Similar results were observed with anti-CD44s. We conclude that the true prognostic significance of CD44v6 overexpression still remains to be shown under rigorous technical conditions (frozen samples, well-documented MAbs, and optimal standardization of procedure using automation and quantitative analysis) providing data appropriate for further correlation with long-term patient follow-up.
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PMID:Automated and quantitative immunocytochemical assays of CD44v6 in breast carcinomas. 904 92

Multidrug resistance in MCF-7/Adr human breast cancer cells is mediated by several mechanisms including overexpression of the MDR1 gene product, P-glycoprotein and glutathione-related detoxifying enzymes. Mutations in the p53 tumor suppressor protein have been reported to play a role in the development of resistance to DNA damaging agents in several human cancer cells. In the present study we have assessed the mutational status of the p53 protein and its expression levels, degree of stability and cellular localization to investigate whether it is involved in modulating multidrug resistance in MCF-7/Adr cells compared to sensitive MCF-7 cells. As revealed by immunofluorescence microscopy using the anti-p53 mouse monoclonal antibody DO-1, wild-type p53 is sequestered in the cytoplasm of MCF-7 cells, whereas in MCF-7/Adr cells, the protein is localized in the nucleus. The sequencing of full-length p53 cDNA revealed a 21 bp deletion in its one of the four conserved regions within the conformational domain, spanning codons 126-133 at exon five, in MCF-7/Adr cells. Moreover, detection of ThaI polymorphism of codon 72 showed that MCF-7 cells predominantly express wild-type p53 with proline, while mutated p53 in MCF-7/Adr cells contains an arginine residue at codon 72. In addition, we demonstrate that the half-life of p53 in MCF-7 cells is less than 30 min while the mutated protein is more stable; its half-life is about 4 h in MCF-7/Adr cells. Thus, this study demonstrates that the deletion of codons 126-133 in p53 causes increased stability, overexpression and nuclear localization of the protein in multidrug resistant MCF-7/Adr cells, and further suggests that mutated p53 might be involved in the development of multidrug resistance in this cell line.
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PMID:Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multidrug resistant MCF-7/Adr human breast cancer cells. 905 47

A role for p53 in the regulation of multidrug-resistance (MDR) has been postulated as wild-type p53 suppresses and mutant p53 specifically activates the mdr1 promoter. Moreover, changes in p53 expression and/or functions could be implicated in drug resistance. As the parental lymphoblastic CCRF-CEM cell line has been described as expressing a mutated form of p53, we have examined p53 and mdm2 protein levels in the human multidrug-resistant CEM-VLB cell line variant. These drug-resistant CEM-VLB cells, which have increased expressions of mdr1 and P-glycoprotein, displayed p53 and mdm2 protein expressions similar to those observed in their sensitive CCRF-CEM counterparts. Treatment of these drug-resistant cells with non-toxic doses of the resistance-inducing drug vinblastin induced a strong increase in p53 protein and mRNA but was ineffective on mdm2 protein expression, or mdr1 mRNA expression. These data indicate that mutant p53 protein was not overexpressed in these MDR cells. This overexpression could be induced by microtubule-active drug treatment, but, as previously observed in other sensitive cell lines, mutant p53 from these MDR cells was unable to positively regulate mdm2 gene product expression.
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PMID:P53 protein expression in human multidrug-resistant CEM lymphoblasts. 911 32

One reason for the failure of chemotherapy is the overexpression of the multidrug resistance gene, MDR1. The product of this gene is the multidrug transporter P-glycoprotein, an ATP-dependent pump that extrudes drugs from the cytoplasm. Some tumors inherently express P-glycoprotein, whereas others acquire the ability to do so after exposure to certain chemotherapeutic agents, often by the mechanism of gene amplification. Classical Wilms' tumors (nephroblastoma) typically respond to therapy and have a good prognosis. On the contrary, anaplastic Wilms' tumors are generally refractory to chemotherapy. These anaplastic variants are rare (4.5% of all Wilms' tumors reported in the United States), aggressive, and often fatal forms of tumor, which are commonly thought to result from the progression of classical Wilms' tumors. To investigate the basis for this differential response to therapy, we examined a number of classical and anaplastic Wilms' tumors for the expression of the MDR1 gene by immunohistochemical and mRNA analysis. Classical Wilms' tumors consistently did not express P-glycoprotein except in areas of tubular differentiation, as in normal kidney. Similarly, two of three anaplastic tumors failed to show P-glycoprotein expression. In contrast, cultured cells derived from a third anaplastic tumor, W4, exhibited strong P-glycoprotein expression and were drug resistant in vitro. Southern analysis revealed that W4 cells contained a single copy of the MDR1 gene per haploid genome similar to normal cells, demonstrating that the overexpression of MDR1 was not caused by gene amplification. Transcriptional activation of the MDR1 gene would be in keeping with the concept that p53 might act as a transcriptional repressor of the MDR1 gene.
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PMID:Anaplasia and drug selection-independent overexpression of the multidrug resistance gene, MDR1, in Wilms' tumor. 912 18

The reduction of E-cadherin expression, which is involved in the initial step of invasion and metastasis of cancer, was investigated in 218 human breast carcinomas. Quantitative immunohistochemical assays (ICAs) were performed on frozen sections. Quantitation was assessed by processing digitized microscopic images of immunoreactions using a computerized system of image analysis (SAMBA). The results were correlated with clinicopathological data and quantitative immunodetection of other molecules. E-cadherin expression was significantly (P < 0.001) stronger in ductal carcinomas than in lobular carcinomas and stronger (P < 0.01) in low grades than in high grades, but E-cadherin was independent of lymph node status and tumour size. Also an inverse significant (P < 0.01) relationship was observed between E-cadherin expression on tissue sections and positive immunoreactions with anti-P53, MIB1 (growth fraction), and anti-c-erb-B2 product. Conversely, strong positive and anti-E-cadherin immunoreactions correlated with strong positive anti-ER and anti-PR immunoreactions (P < 0.01). No relationship was observed between E-cadherin and the results of quantitative ICAs of cathepsin D, CD31, and P-glycoprotein, assessed on consecutive sections from the same frozen tissue samples. The results show that preserved E-cadherin expression correlates with high degree of tumour differentiation, low proliferative activity, and low expression of prognostic markers. The deregulation of E-cadherin is independent of other steps of tumour invasion, such as protease digestion of extracellular matrix and angiogenesis.
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PMID:E-cadherin quantitative immunocytochemical assays in breast carcinomas. 915 15

Contemporary therapies for acute myeloid leukemia (AML) commonly fail to cure patients because of the emergence of drug resistance. Drug resistance in AML is multifactorial but can be associated with the overexpression of transmembrane transporter molecules, including P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP), or associated with inactivation of the p53 tumor suppressor gene, as well as overexpression of the anti-apoptotic protein bcl-2. We are investigating if novel recombinant biotherapeutics can circumvent these resistance mechanisms to effectively treat refractory AML. To target the lethal action of diphtheria toxin (DT) to high affinity granulocyte-macrophage colony-stimulating factor (GMCSF) receptors on AML blasts, we have produced a recombinant chimeric fusion toxin, DTctGMCSF. Since DTctGMCSF enters and kills its target cells by unique mechanisms (GMCSF-receptor binding and protein synthesis inhibition) and is not similar in structure to Pgp or MRP substrates, we postulated that it would be an active agent against therapy-resistant AML. DTctGMCSF was selectively cytotoxic (IC50 1-10ng/ml) to GMCSF-receptor positive AML cells expressing the Pgp- or MRP-associated multi-drug resistant phenotypes, despite high level resistance to conventional chemotherapeutic agents. DTctGMCSF also efficiently killed AML cells deficient in p53 expression, as well as radiation-resistant AML cells and mixed lineage leukemia cells expressing high levels of bcl-2. In addition, DTctGMCSF killed > 99% of primary leukemic progenitor cells from therapy-refractory AML patients under conditions that we have previously found to not adversely affect the proliferative capacity or differentiation of pluripotent normal hematopoietic progenitor cells. DTctGMCSF may prove useful in treating myeloid leukemias that are otherwise resistant to a wide range of conventional therapies.
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PMID:Granulocyte-macrophage colony-stimulating factor receptor-targeted therapy of chemotherapy- and radiation-resistant human myeloid leukemias. 916 35

The expression of the MDR1 gene has been shown to correlate with tumor aggressiveness and oncogenic activation both in experimental tumor models and in human clinical specimens In order to verify whether this association also takes place in ovarian carcinoma, we studied tumor samples from 39 patients by means of immunohistochemistry for the overexpression of P-glycoprotein (MDR1), nm23, c-erb-B2 and p53. MDR1 (p = 0.023), nm 23 (p = 0.037) and c-erb-B2 (p = 0.015) were expressed significantly more in specimens from patients with advanced stage of disease. There were no differences in p53 expression between both groups of patients. Furthermore, we found a significant coexpression of MDR1 and nm23 (p = 0.028), and of MDR1 and c-erb-B2 (p = 0.0077). There was no association between the expression of the MDR1 gene and p53. These results parallel those previously reported by us for mammary carcinoma, and seem to indicate that expression of the multidrug resistance gene (MDR1) is inherent to the development of the malignant phenotype in several human tumors.
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PMID:Correlation of MDR1 expression and oncogenic activation in human epithelial ovarian carcinoma. 921 79

Hepatocellular carcinoma (HCC), a chemoresistant tumour, is the most common fatal cancer in Taiwan. Hepatocellular carcinoma frequently expresses a high level of P-glycoprotein (P-gp), which is a specific phenotype of a multidrug-resistance gene, and harbours mutations of the tumour suppressor gene p53. A modulatory relationship between p53 and P-gp has been reported. In this study, we analysed the expression of P-gp in relation to chemotherapeutic response and p5353 protein expression in advanced HCC. Prechemotherapeutic tumour samples were obtained from 25 patients with HCC which had been treated with either etoposide (VP-16) or doxorubicin. P-glycoprotein and p53 in HCC were visualized by immunohistochemical staining using the monoclonal antibodies JSB-1 and DO1, respectively. We investigated the correlation of P-gp expression with chemotherapeutic responses, clinicopathological features and p53 protein expression. In our study, seven cases achieved partial remission, and the remaining 18 cases had a poor response to chemotherapy. Expression of P-gp was observed in 13 tumours (52%). Positive P-gp protein expression was significantly associated with non-responders (8% or 1/13 vs 50% or 6/12, P = 0.03). Thus, P-gp expression inversely correlated with chemotherapeutic response. Expression of p53 protein was seen in 12 cases and did not correlate with chemosensitivity or P-gp expression. In summary, P-gp expression correlates with the chemosensitivity of HCC that has been treated with VP-16 or doxorubicin and p 53 mutations do not appear to be a major determinant of P-gp expression in advanced HCC.
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PMID:Expression of P-glycoprotein and p53 in advanced hepatocellular carcinoma treated by single agent chemotherapy: clinical correlation. 930 8

The relevance of continuous cell line cultures to the problem of clinical anticancer drug resistance is unclear. There is also mounting scepticism regarding the use of tumour cell lines with in vitro acquired drug resistance, possessing high levels of resistance unlikely to be seen in the clinical setting. To overcome some of these problems we have initiated a study of drug resistance using fresh tumour material obtained from patients suffering from ovarian cancer and soft tissue sarcoma (STS). Studies involving ovarian cancer have involved over 30 specimens of stage III-IV disease. For these samples we have specifically focused on the multidrug-resistant (MDR) phenotype, examining the role of proteins P-glycoprotein (Pgp), multidrug resistance-protein (MRP) and lung-resistance-associated protein (LRP). Techniques have involved chemosensitivity testing, immunocytochemistry and flow cytometry, to measure Pgp function (drug efflux capacity with modulator reversal). Pgp was the most commonly expressed marker and its expression correlated with survival. MDR modulation using cyclosporins was shown to chemosensitise a proportion of the samples. Hence, in vitro screening can help to identify patients likely to benefit from resistance reversal strategies. Studies involving STS have looked at a combination of MDR and p53 disruption (commonly seen in this disease). Data have been examined alongside clinical data and the course of disease has been closely monitored. Although our studies are ongoing, we have identified a group of patients with aggressive disease showing marked drug resistance in vitro. All patients have relapsed with persistent disease following chemotherapy or radiotherapy. A number of chemoresistant patients showed a combination of p53 disruption in the presence of an MDR phenotype. Feedback from these translational studies should be used to guide the selection of patients for clinical trials using resistance reversal strategies and may suggest new targets for drug development.
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PMID:Drug resistance studies using fresh human ovarian carcinoma and soft tissue sarcoma samples. 933 43


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