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)

In this investigation, untreated non-B-type acute lymphoblastic leukemia (ALL) of 104 children was analyzed using immunocytochemistry for expression of protein kinase C, proto-oncogene products (Fos, Jun, Ras) and resistance-related proteins (topoisomerase II, P-glycoprotein, glutathione S-transferase-pi, metallothionein, dihydrofolate-reductase, thymidylate-synthase). The aim of the analysis was to find out whether combining those factors with the most important clinical prognostic factor (blast cell count) can improve the prognostic value (relapse-free interval). Univariate analysis shows that protein kinase D (PKC), Fos, P-glycoprotein (P-170) and glutathione S-transferase-pi (GST-pi) are significant prognostic factors independent of blast cell count (PBC) for the relapse-free intervals of children with ALL. The presence of the proteins Fos, PKC, P-170 and GST-pi was not independent within the patient population. The multivariate analysis showed that in combination with PBC and PKC, both P-170 and GST-pi have only limited prognostic influence. Combining the factors PKC, Fos and GST-pi as a categorical variable showed that this variable is a strong prognostic factor in addition to PBC.
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PMID:Prognostic value of protein kinase C, proto-oncogene products and resistance-related proteins in newly diagnosed childhood acute lymphoblastic leukemia. 898 47

Twenty tumoral and peritumoral tissues from patients with lung cancer were analyzed immunohistochemically for the drug resistance-related proteins P-glycoprotein (P-170), topoisomerase II (Topo-II), glutathione S-transferase-pi (GST-pi), metallothionein (MT), heat shock protein-70 (HSP-70) and the putative regulators of resistance (ErbB1, Fos and Jun). Protein expression of Topo-II, GST-pi, MT, HSP-70, ErbB1, Fos and Jun was elevated in tumor tissue in comparison to normal tissue. The different expression of the proteins between tumoral and normal tissues was statistically significant for Topo-II (P = 0.05), MT (P = 0.03), and HSP-70 (P = 0.01), whereas ErbB1 showed a borderline significance. The expression of the proteins was frequently increased in smokers in comparison to non-smokers. In general, the increase of the proteins of smokers corresponded in tumoral and non-tumoral tissue. Different expression was only found with MT and HSP-70 which were higher in tissues of smokers.
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PMID:Expression of resistance-related proteins in tumoral and peritumoral tissues of patients with lung cancer. 901 91

The expression of different genes potentially involved in DNA repair and in cell responses to chemotherapy was evaluated in 33 previously untreated ovarian cancer patients. In biopsies of the same patients the expression of repair genes O6-methylguanine DNA methyltransferase (MGMT), 3-methyladenine DNA glycosylase (MAG), ERCC1, MDR-1, DNA topoisomerase I, DNA topoisomerase IIalpha, and glutathione S-transferase-pi (GST-pi) was assessed by Northern blot analysis. No direct statistical correlation was found between the expression of these genes and the response to chemotherapy (mainly platinum-based with or without doxorubicin and cyclophosphamide). Univariate analysis showed a weak negative correlation (P = 0.037) between the expression of ERCC1 and mortality, whereas no statistically significant correlation was found for other parameters. The MDR-1 gene encoding for the P-glycoprotein P-170 was mostly undetectable in these patients (as assessed by Northern blotting), whereas relatively high levels of MAG and MGMT were found in the majority of patients. A statistically significant correlation was found between the expression of DNA topoisomerase I and the expression of either ERCC1 (P = 0.0026) or GST-pi (P = 0.0279).
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PMID:Expression of genes of potential importance in the response to chemotherapy and DNA repair in patients with ovarian cancer. 910 2

Resistance of tumor cells to chemotherapeutic drugs can not only be caused by treatment with antineoplastic agents but also by radiotherapy. The aim of this study was to analyze whether ionizing radiation can influence the mRNA expression of proteins which have been found to be involved in drug resistance of tumor cells. Human tumor cell lines (MCF-7, LXF and Sk-Mel) were treated with single doses of irradiation (5, 10 and 20 Gy). The expression of the resistance related proteins glutathione S-transferase-pi (GST-pi), topoisomerase II alpha (Topo II), thymidylate synthase (TS), O6-methylguanine-DNA-methyltransferase (MGMT), P-glycoprotein (Pgp), glutathione peroxidase (GPX) multidrug resistance-associated protein (MRP) and also of the heat-shock protein 70 (HSP 70) were determined at the mRNA level during the time interval from 1.5 to 72 h post-irradiation and compared with their corresponding controls. We also examined whether a relationship exists between these proteins and the proliferative activity (histone 3, Ki-67, statin) of the cells. We found that exposure of MCF-7, LXF and Sk-Mel cells to ionizing radiation increases the expression of the mRNA of GST-pi. Topo II, TS, HSP 70 and proliferation markers were also altered by exposure to ionizing radiation, but there was no common response of the three cell lines. No significant changes were observed in the expression of MGMT, Pgp, GPX and MRP after radiation treatment. Drug resistance tests revealed that irradiated MCF 7 cells were less sensitive to doxorubicin than non-irradiated control cells. Our results indicate that ionizing irradiation modifies the expression of some proteins involved in drug resistance and the response of MCF 7 cells to doxorubicin and may, therefore, play a role in clinical drug response.
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PMID:Messenger RNA expression of resistance factors in human tumor cell lines after single exposure to radiation. 941 87

The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil (5-FU) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center. Three markers of possible platinum chemotherapy association [metallothionein (MT), glutathione S-transferase-pi (GST-pi), P-glycoprotein (P-gp or multidrug resistance)] and one marker of possible 5-FU association [thymidylate synthase (TS)] were measured using immunohistochemistry. The median cancer-free survival was 25.0 months, with a significantly improved survival for the 38 patients who had a complete response (P < 0.001). High-level expression of GST-pi, P-gp, and TS were associated with a decreased survival. MT was not significant in this population. Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death. In conclusion, this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from trimodality therapy. These data need to be reproduced in a prospective investigation.
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PMID:The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. 1129 49

Multidrug resistance in human ovarian carcinoma cell lines is caused by the expression of several related proteins, namely P-glycoprotein 170 (Pgp-170), glutathione S-transferase-pi GST-pi), and thymidylate synthase (TS). These proteins seem to be regulated by a common mechanism in which the expression of protein kinase C (PKC) is involved. Additionally, the function of Pgp-170 is dependent on PKC phosphorylation. However, in ovarian carcinoma cell lines the role of different PKC enzymes responsible for resistance is not quite clear. In the present study we circumvented resistance in taxol resistant human ovarian carcinoma cell lines with antisense oligonucleotides to PKC alpha and PKC beta mRNA and compared the effects with those obtained by Pgp-170 antisense oligonucleotides. We found a significant inhibition of cell number after treatment with Pgp-170 antisense oligonucleotides in combination with taxol. Additionally, resistance could be reversed by treatment with taxol and antisense oligomers to PKC alpha and PKC beta. This shows that regulatory correlations between these proteins exist and that inhibition of the mRNA of PKC alpha and PKC beta isoforms and Pgp-170 can reverse multidrug resistance.
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PMID:Modulation of multidrug resistance in human ovarian cancer cell lines by inhibition of P-glycoprotein 170 and PKC isoenzymes with antisense oligonucleotides. 1241 18

Xenobiotic efflux pumps at the blood-brain barrier are critical modulators of central nervous system pharmacotherapy. We previously found expression of the ligand-activated nuclear receptor, pregnane X receptor (PXR), in rat brain capillaries, and showed increased expression and transport activity of the drug efflux transporter, P-glycoprotein, in capillaries exposed to PXR ligands (pregnenolone-16alpha-carbonitrile (PCN) and dexamethasone) in vitro and in vivo. Here, we show increased protein expression and transport activity of another efflux pump, multidrug resistance-associated protein isoform 2 (Mrp2), in rat brain capillaries after in vitro and in vivo exposure to PCN and dexamethasone. The phase-II drug-metabolizing enzyme, glutathione S-transferase-pi (GSTpi), was found to be expressed in brain capillaries, where it colocalized to a large extent with Mrp2 at the endothelial cell luminal plasma membrane. Like Mrp2, GSTpi protein expression increased with PXR activation. Colocalization and coordinated upregulation suggest functional coupling of the metabolizing enzyme and efflux transporter. These findings indicate that, as in hepatocytes, brain capillaries possess a regulatory network consisting of nuclear receptors, metabolizing enzymes, and efflux transporters, which modulate blood-brain barrier function.
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PMID:Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood-brain barrier. 1834 76

Resistance to chemotherapy agents is the main reason for treatment failure in patients with cancer. Multidrug resistance (MDR) is the primary mechanism that leads to the acquisition of the multiresistant phenotype through the overexpression of drug efflux transporters such as the P-glycoprotein (Pgp), encoded by the MDR1 gene, at the plasma membrane. Other molecules that have been implicated in drug resistance include multidrug resistance-associated proteins, glutathione S-transferase-pi, and DNA topoisomerase II. These molecules, however, cannot fully explain MDR in oral squamous cell carcinoma. Vacuolar ATPase (V-ATPase), which is largely responsible for regulating acidity in the microenvironment of solid tumors (and hence interfering with the absorption of chemotherapy drugs), seems to be the most important molecule involved in MDR in such tumors. Specific V-ATPase inhibitors, thus, may be useful, not only as coadjuvants in antitumor treatments but also as a mechanism for controlling resistance to antitumor drugs.
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PMID:Multidrug resistance in oral squamous cell carcinoma: The role of vacuolar ATPases. 2041 15

One hundred and eleven children with initial ALL and 28 children with relapsed ALL were analyzed immunohistochemically for expression of resistance-related proteins. P-glycoprotein (P-170) was found in 35% (initial ALL) vs 54% (relapsed ALL; p=0.07), glutathione S-transferase-pi (GST) in 49% vs 68% (p=0.07), thymidylate-synthase (TS) in 42% vs 64% (p=0.03), dihydrofolate-reductase (DHFR) in 20% vs 32% and metallothionein (MT) in 33% vs 32% of the cases. In initial ALL, the resistance proteins P-170 and GST were expressed more frequently in patients who relapsed under therapy and the frequency was similar to relapsed ALL. These results indicate that P-170 and GST-pi were already present before treatment. In contrast, expression of TS increased during treatment.
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PMID:Resistance-related proteins in initial and relapsed childhood acute lymphoblastic leukemia. 2154 64

Drug resistance related proteins P-glycoprotein (P170), multidrug resistance associated protein (MRP), glutathione S-transferase-pi (GST-pi), glutathione peroxidase (GPX), topoisomerase II (Topo II), thymidylate synthase (TS), O-6-methylguanine-DNA-methyltransferase (MGMT), the heat shock proteins HSP27 and HSP70 and the protooncogenes Fos, Jun and EGFR were investigated in human lung carcinomas and matched normal tissues. We found that the mRNA expression of Topo II and TS were elevated in tumor tissue versus corresponding normal tissue. Additionally Topo II and TS correlated with the proliferating activity determined by expression of histone 3. P170, MRP, HSP70 and also EGFR mRNA were elevated in some tumor probes, but not GST-pi, GPX, MGMT and HSP27 mRNA. Additionally, we determined various values of Fos and Jun mRNA expression but there was no uniform pattern. The finding that some proteins were abnormally expressed in lung tumors compared to the adjacent normal tissue is an important finding for further investigations on the development of individualized chemotherapy but more samples should be examined to extend these observations.
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PMID:Comparison of the mRNA expression of factors related to drug resistance in lung tumors and adjacent normal tissue. 2154 93


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