Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of the drug resistance markers P glycoprotein (P-170), glutathione S transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) was analyzed in 16 human kidney carcinoma cell lines, 18 hematological malignancies, and 14 human breast carcinomas. We found a tendency for coexpression of increased P-170 and GST-pi and of increased P-170 and decreased Topo II expression in kidney carcinoma cell lines. A similar tendency was found between P-170 and GST-pi expression in breast carcinomas. In contrast, hematological malignancies did not show such a coexpression of resistance markers. Furthermore, we found interrelationships between the expression of resistance markers, resistance to doxorubicin or vincristine, and doubling times of kidney carcinoma cell lines. This indicates that the proliferative activity of tumor cells plays a role for the expression of resistance markers and the development of resistance to cytostatic drugs.
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PMID:Immunohistochemical detection of P glycoprotein, glutathione S transferase and DNA topoisomerase II in human tumors. 135 60

In this report we analyzed the mRNA expression of the resistance-related enzymes DNA topoisomerase II (Topo II), thymidylate synthase (TS), glutathione S-transferase-pi (GST-pi) and glutathione peroxidase (GP) in childhood acute lymphoblastic leukemia (ALL) and their correlation to the proliferative activity, determined by Ki-67. RNA of blast cells from 54 children with untreated ALL were examined by dot blot hybridization. We found a significant positive correlation between Topo II and TS and cell proliferation. No significant correlation was detected between the mRNA expression of the glutathione-dependent enzymes GST-pi or GP and Ki-67. The results were substantiated by a semiquantitative RT-PCR-assay and by immunocytochemistry.
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PMID:Messenger RNA expression of resistance factors and their correlation to the proliferative activity in childhood acute lymphoblastic leukemia. 788 95

A subline highly resistant to Adriamycin (SBC-3/ADM100) was isolated in vitro from the human small cell lung cancer cell line, SBC-3, by culturing in progressively higher concentrations of Adriamycin. The SBC-3/ADM100 cells were 106-fold more resistant to the drug than the parent cells in an inhibitory concentration of 50% determined by the MTT assay. The population-doubling time was much longer in SBC-3/ADM100 than in the parent cells. Northern blot hybridization revealed marked overexpression of the MDR1 mRNA in the resistant cells. P-glycoprotein overexpression and a decrease in intracellular accumulation of Adriamycin were demonstrated in SBC-3/ADM100, indicating that outward drug transport was the major mechanism of resistance in this subline. Additionally, a significant elevation of the intracellular glutathione content coupled with the glutathione S-transferase (GST) pi level and a decrease in DNA topoisomerase II (Topo II) activity were noted in this resistant subline. These results indicate that the mechanism of resistance to Adriamycin is multifactorial; involving altered growth characteristics, an enhanced outward transport, enhanced drug detoxification process, and decreased target enzyme activity. The resistant subline will serve as a useful tool in the search for ways to overcome drug resistance.
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PMID:Establishment of an adriamycin-resistant subline of human small cell lung cancer showing multifactorial mechanisms of resistance. 810 72

Drug-resistance in cell lines and in malignant human tumours is associated with dysregulation of several genes including mdr1, MRP1, GST-pi, bcl-2, DNA topoisomerase II alpha and beta, and thymidine kinase I. mRNA expression was evaluated by quantitative RT-PCR coupled with HPLC in three human tumour cell lines and drug-resistant (DR)-sublines. DR sublines from RPMI-8226 and KB cells specifically overexpressed the mdr1 gene without major changes observed in other putative DR-associated genes. In contrast, the DR-H69 cells exhibited a 34-fold overexpression of the MRP gene accompanied by significant down-regulation of both DNA topoisomerase II alpha and bcl-2 mRNA gene expression, by factors of 43 and 13 respectively. These results demonstrate the concomitant down regulation of topoisomerase II alpha and bcl-2 genes in response to DR. Furthermore, differential patterns of gene dysregulations appear to vary depending upon both the drug used to select resistance and cellular origin.
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PMID:Assessment of drug-induced dysregulations among seven resistance-associated genes in human tumour cell lines. 904 17

We cloned a gene (topA) encoding DNA topoisomerase II from Dictyostelium discoideum nuclear DNA using oligo probes corresponding to the consensus amino acid sequences found in the gene in other eukaryotes. The gene encoding a predicted polypeptide of 1282 amino acids with M(r) of about 146 kDa, is a single copy that is expressed as a polyadenylated 4.5 kb RNA. The predicted amino acid sequence shares similarity with those of other eukaryotes with identity between 32 and 46%. The protein is 260-300 amino acids shorter in the C-terminal region and 50-80 longer in the N-terminal region than those of other eukaryotes. In TopA of D. discoideum, the N-terminal region with stretches of charged and hydrophilic amino acids is predicted to fold into an amphiphilic alpha-helix which is characteristic of a mitochondrial targeting signal presequence. Four independent polyclonal antibodies against bacterially expressed GST fusion proteins containing four portions of the polypeptide detected a single band on Western blots at about 135 kDa. Western blots analysis of subcellular fractions revealed that this protein is localized in mitochondria. The protein and the mRNA are present in growth phase and during development, although levels of both declined as development proceeded.
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PMID:Cloning and characterization of the gene encoding a mitochondrially localized DNA topoisomerase II in Dictyostelium discoideum. Western blot analysis. 917 84

DNA topoisomerase II-an essential nuclear enzyme in DNA replication and transcription, chromatin segregation, and cell cycle progression-is also a target of clinically useful anticancer drugs. Preliminary observations of a positive correlation between the expression of topoisomerase (topo) IIalpha and the retinoblastoma protein (Rb) in a series of rhabdomyosarcoma cells prompted us to ask whether these two proteins interact in vivo. Using human rhabdomyosarcoma and leukemic cell lines, we found a physical association between topo IIalpha and Rb protein by reciprocal immunoprecipitation and immunoblotting, in which topo IIalpha appeared to interact primarily with the underphosphorylated form of Rb. Experiments with truncated glutathione S-transferase-Rb fusion proteins and nuclear extracts of Rh1 rhabdomyosarcoma cells indicated that topo IIalpha binds avidly to the A/B pocket domain of Rb, which contains the intact spacer amino acid sequence. To determine whether this interaction has functional consequences in vivo, we expressed wild-type and mutant Rb in human cervical carcinoma cells lacking functional Rb. Wild-type, but not mutant, Rb inhibited topo II activity in nuclear extracts of these transfected cells. Moreover, purified wild-type Rb inhibited the activity of purified human topo IIalpha, indicating a direct interaction between these two proteins. We conclude that topo IIalpha associates physically with Rb in interactions that appear to have functional significance.
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PMID:Functional interaction between human topoisomerase IIalpha and retinoblastoma protein. 1039 12

DNA topoisomerase II (topo II) is a ubiquitous nuclear enzyme that is involved in DNA replication, transcription, chromosome segregation, and apoptosis. Here we show by immunoprecipitation, pull down with glutathione S-transferase fusion proteins, and yeast two-hybrid analysis that both topo IIalpha and -beta physically interact with the histone deacetylase HDAC1. The in vitro DNA decatenation activity of recombinant topo IIalpha and -beta is inhibited by association with catalytically inactive, recombinant HDAC1. We provide evidence for the in vivo significance of the topo II-HDAC1 association, showing that inhibition of HDAC activity with trichostatin A suppresses apoptosis induced by the topo II poison etoposide, but not by the topoisomerase I inhibitor camptothecin. We suggest that chromatin remodeling by an HDAC-containing complex facilitates both topo II-catalyzed DNA rearrangement and etoposide-induced DNA damage in vivo.
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PMID:Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis. 1113 18

More than 80% of the patients presenting with Wilms' tumor can be cured today. Some patients, however, fail to respond to chemotherapy. The objective of this study was to analyze the immunohistochemical distribution of two markers of cytostatic drug resistance, e.g. DNA topoisomerase II alpha (Topo II alpha) and glutathione S-transferase-pi (GST-pi) in 23 Wilms' tumor patients who had undergone an operation between 1984 and 1997. Eight patients had stage I disease, seven stage II, three stage III, four stage IV, and one stage V disease. Five tumors showed high malignancy histology. Investigations were carried out on formalin-fixed and paraffin-embedded tissue sections using the indirect immunoperoxidase method. Topo II alpha was predominantly present in the epithelial components of the specimens. It was more frequently found in anaplastic tumors. There was no difference in the presence of Topo II alpha in the epithelial components between specimens derived from treated and untreated patients. Topo II alpha was, however, less expressed in the blastemal and stromal elements of specimens after preoperative treatment. If GST-pi was present, it was confined to the epithelial components except for one case. While no expression of GST-pi was found in preoperatively untreated Wilms' tumors, it was present in epithelial compartments in 57% of tumors after chemotherapy. In conclusion, preoperative chemotherapy led to compartment-specific alterations in the expression levels of both markers indicating a contribution to treatment response of Wilms' tumors.
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PMID:Differential expression of the drug resistance markers DNA topoisomerase II alpha and glutathione S-transferase-pi in the histological compartments of Wilms' tumors. 1129 42

To characterize the multidrug resistance (MDR) phenotype in human oral squamous cell carcinomas (OSCCs), the expression levels of four MDR-related genes (multidrug resistance, mdr1; multidrug resistance-associated protein, MRP; glutathione S-transferase-pi, GST-pi; and DNA topoisomerase II, topoII) were analyzed in OSCCs. Fifty-two OSCC tissues and 22 normal oral mucosal tissues were involved in this study. The expression of each gene was analyzed with a reverse-transcription polymerase chain reaction (RT-PCR) method using beta(2)m microglobulin (beta(2)m) mRNA as an endogenous control. The mean values of mdr1, MRP, GST-pi, and topoII gene expression relative to the beta(2)m gene in OSCC tissues were 0.37, 0.75, 0.66, and 1.11; those of normal oral mucosa were 0.40, 0.27, 0.62, and 0.91, respectively. The averaged expression levels of the MRP and topoII gene in OSCC tissues were higher than those of normal oral mucosas (P=0.001 and P=0.02, respectively). The expression levels of four MDR-related genes in OSCCs were not related with the degree of histologic cell differentiation, tumor stage, primary or recurred tumor, or the presence or absence of chemotherapy. Linear regression analysis showed a correlation between the expression levels of MRP and GST-pi in normal oral mucosas (r=0.596, P=0.003) and in OSCCs (r=0.287, P=0.039). The results suggest that MRP expression is activated during the tumorigenesis of OSCCs and that this may play a role in de novo drug resistance in OSCCs. These results should provide further insight into the complex role postulated for MDR-related genes in chemotherapy, carcinogenesis and tumor progression.
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PMID:Expression of multidrug resistance-related genes in oral squamous cell carcinomas. 1159 75

This study aims to investigate the expression of P-glycoprotein (PGP), glutathione S-transferase pi (GST-pi), DNA topoisomerase II (Topo-II) and lung resistance-related protein (LRP) in ovarian carcinoma, thus providing better chemotherapy choice and post-operative prognosis for ovarian carcinoma patients. A total of 80 primary ovarian carcinoma, 16 benign ovarian epithelial neoplasm, and 12 normal ovarian tissue samples were collected. Immunohistochemistry was used to detect the expression of PGP, GST-pi, Topo-II and LRP, and the results were analysed by correlation with clinicopathological parameters. Positive expression rates of PGP, GST-pi, Topo-II and LRP in patients with ovarian carcinoma (57.5%, 58.8%, 76.3% and 73.8%, respectively) were all higher than those found in normal and benign tissue (P<0.05). In clinical stages I/II vs. III/IV, the expression rates of PGP, GST-pi, Topo-II and LRP were 40.7% vs. 66% (P<0.05), 40.7% vs. 67.9% (P<0.05), 66.7% vs. 81.1% (P>0.05) and 55.6% vs. 83.0% (P<0.05), respectively. Carcinoma differentiation ranged from well to poor, and expression levels of each marker were as follows: PGP, 57.9%, 62.1% and 53.1% (P>0.05); GST-pi, 36.8%, 55.2% and 75.0% (P<0.05); Topo-II, 52.6%, 79.3% and 87.5% (P<0.05); and LRP, 84.2%, 69.0% and 71.9% (P>0.05). Ovarian carcinoma patients with PGP-, GST-pi-, Topo-II- and LRP-positive expression had a shorter median survival time than those who were negative for these markers (PGP: 36 months vs. 48 months [P=0.0017]; GST-pi: 36 months vs. 41 months [P=0.0103]; Topo-II: 37 months vs. 39 months [P=0.3811]; LRP: 37 months vs. 55 months [P=0.002]). COX regression analysis demonstrated that the clinical stage of the tumour, and the expression of PGP, GST-pi or LRP, may influence patient survival time after surgery. The relative death risk for patients with clinical stage III/IV tumours increased 9.46-fold compared to those with stage I/II tumours. The relative death risk in the PGP-, GST-pi- and LRP-positive groups increased by 2.049-, 2.452- or 2.609-fold, respectively, compared with the corresponding negative groups. PGP, GST-pi, Topo-II and LRP are all expressed in primary ovarian carcinoma, indicating the presence of multidrug resistance in this disease. Combined evaluation of PGP, GST-pi, Topo-II and LRP expression may enable better chemotherapeutic choice and provide an accurate prognosis for ovarian carcinoma patients.
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PMID:Multidrug resistance-associated biomarkers PGP, GST-pi, Topo-II and LRP as prognostic factors in primary ovarian carcinoma. 2170 17


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