Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the factors contributing to tumor sensitivity to adriamycin (ADR) in vivo, the relationship between mRNA expression of the MDR1, GST-pi and topoisomerase II genes and tumor response to ADR was examined in six human xenograft tumors derived from two esophageal, two gastric and two colon cancers. A significant tumor response to ADR was observed in two esophageal xenograft tumors of six tumor lines, and one gastric tumor partially responded to ADR. mRNA expression of the MDR1 and GST-pi genes was elevated in five tumor lines including three ADR responsive tumors, whereas mRNA expression of the topoisomerase II gene was detected in all six tested tumor lines. Topoisomerase II mRNA expression levels in ADR responsive tumors were higher compared with those of ADR unresponsive tumors. No significant relationship between mRNA expression of the MDR1 and GST-pi genes and ADR sensitivity was found. In contrast, topoisomerase II mRNA expression was significantly correlated with tumor sensitivity to ADR (p less than 0.01). Moreover, topoisomerase II mRNA expression was significantly correlated with the growth fraction (S-phase fraction) in the cell cycle kinetics (p less than 0.01). These results indicate that topoisomerase II mRNA expression in association with the high growth fraction may be an important in vivo factor to contribute to ADR sensitivity in human tumors.
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PMID:Factors contributing to adriamycin sensitivity in human xenograft tumors: the relationship between expression of the MDR1, GST-pi and topoisomerase II genes and tumor sensitivity to adriamycin. 131 32

The usefulness of MDR1, GST-pi or topoisomerase II mRNA expression detected by dot blot analysis as an indicator of intrinsic resistance to adriamycin was investigated in 15 fresh human tumor specimens. MDR1 and GST-pi expression, which is known to be a marker for adriamycin resistance, was detected in six (66.7%) and seven (77.8%) of the nine clinically resistant tumors, respectively. However, in four of the six adriamycin responsive tumors, MDR1 and/or GST-pi expression were detected. Thus these two markers were not indicators of clinical response to adriamycin. In contrast, topoisomerase II mRNA expression was significantly correlated with clinical response (p less than 0.01, chi 2 test). The expression of topoisomerase II mRNA was detected at a high level in five (83.3%) of the 6 clinically responsive tumors, and the other nine tumors resistant to adriamycin treatment exhibited undetectable or low levels of topoisomerase II mRNA. We therefore suggest that the level of topoisomerase II mRNA expression is a useful marker of the clinical response to adriamycin.
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PMID:Expression of MDR1, GST-pi and topoisomerase II as an indicator of clinical response to adriamycin. 185 Feb 21

After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Anthracyclines. 222 2

The expression of drug resistance-associated mdr-1, GST pi, and topoisomerase II genes was analyzed in cell cycle phase enriched populations of doxorubicin-resistant murine leukemic P388/R-84 cells. Flow cytometric analysis of bromodeoxyuridine (BrdU) incorporation and staining with anti-BrdU antibodies was used to confirm the purity of cell cycle phase enriched populations obtained by centrifugal elutriation. Doxorubicin (DOX) and daunorubicin (DNR) accumulation was significantly lower in S-phase cells, and coincubation with verapamil (VPL) or chlorpromazine (CPZ) enhanced DOX and DNR accumulation more in S-phase than in G1- and G2/M-phase cells. While the cellular content of mdr-1 and topoisomerase II mRNAs changed, GST pi mRNA content remained constant during the cell cycle. S-phase cells had about 3-fold higher mdr-1 mRNA content than G1- and G2/M-phase cells. In G1 cells, P-glycoprotein expression, as determined by C219 monoclonal antibody, was 12% less than that of S and G2/M cells. Topoisomerase II mRNA content increased with the progression of cell cycle and peaked in G2/M cells. These observations suggest that cell cycle stage related changes in expression of drug resistance markers may have a major bearing on chemosensitivity of drug-resistant cells.
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PMID:Expression of drug resistance-associated mdr-1, GST pi, and topoisomerase II genes during cell cycle traverse. 787 60

In order to clarify the mechanism of drug resistance in human myeloma cells, we investigated the expressions of DNA topoisomerase I and topoisomerase II gene and the genes possibly related to drug resistance; multi-drug resistant gene 1 (MDR-1), glutathione S-transferase class pi gene (GST-pi), by Northern blotting. Myeloma cells in eight of 15 cases prior to chemotherapy expressed topoisomerase I mRNA considerably, while the expression of topoisomerase II mRNA was detected weakly in only one of 16 myeloma patients. There was not any correlation between expression of topoisomerase I mRNA and clinical drug resistance. Significant expression of MDR-1 mRNA and P-glycoprotein was not detected in 25 cases of multiple myeloma prior to chemotherapy and even after several courses of VAD (vincristine, adriamycin and dexamethasone) therapy by Northern blotting and immunostaining using monoclonal anti-P-glycoprotein antibody (MRK-16), respectively. On the other hand, 16 of 21 myeloma cases showed significant expression of GST-pi protein and GST-pi mRNA with the various strengths, but there was no apparent correlation between GST-pi mRNA expression and clinical response. Therefore these data suggest that expression of the genes we tested may not determine the level of drug resistance in multiple myeloma, but lower or no significant expression of topoisomerase II mRNA in most myeloma cells indicates the possibility that topoisomerase II inhibitors such as VP-16 and topoisomerase II-mediated cytotoxic drugs such as adriamycin, are not so effective for the treatment of multiple myeloma.
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PMID:Expressions of DNA topoisomerase I and II gene and the genes possibly related to drug resistance in human myeloma cells. 809 26

We investigated four mechanisms of intrinsic chemoresistance in a series of 67 human brain tumours including 31 gliomas (one grade I ganglioglioma, nine grade II and 10 grade III astrocytomas, 11 glioblastomas), 13 cerebral metastases, one medulloblastoma, one malignant teratoma, three ependymomas and 18 meningiomas. We studied four genes by northern blotting: multidrug-resistance (MDR 1), glutathione-s transferase (GST pi), dihydrofolate reductase (DHFR), and topoisomerase II (Topo II). The Topo II gene was absent in the normal adult brain (100%) and in 64% of the tumour samples tested. A second gene, GST pi, was found to be overexpressed in 38% of brain tumours. The two other chemoresistance-related genes were occasionally overexpressed in brain tumours (2% for MDR1, 9% for DHFR). Our results provide evidence that chemoresistance is intrinsic to the brain tissue and seems likely to be a multifactorial process.
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PMID:A study of the expression of four chemoresistance-related genes in human primary and metastatic brain tumours. 838 72

The aim of the present study was to potentiate the cytotoxic effects of melphalan through pharmacological and physical modulators. The combination of the cytotoxic agent with ethacrynic acid, a glutathione-S-transferase pi (GST pi) inhibitor, or topotecan, a topoisomerase I inhibitor, or mild hyperthermia was investigated. The selected cell lines exhibited variable levels of expression of GST pi, DNA topoisomerase I and heat-shock proteins. Mild hyperthermia (42 degrees C) alone potentiated melphalan cytotoxicity, especially in the two cell lines exhibiting low basal levels of HSP70 expression. The combination of the GST inhibitor with melphalan resulted in a potentiation of drug cytotoxicity only in JR8 cells, one of the two cell lines which expressed high levels of GST pi mRNA and which were the less responsive to ethacrinic acid alone. A synergistic interaction between topotecan and melphalan was observed only in the cell lines expressing low levels of topoisomerase I even if all cell lines exhibited a comparable sensitivity to this agent. The results support an involvement of GST and DNA topoisomerase in cell defense and response to the alkylating agent. However, the variable potentiation of the cytotoxic effects of melphalan achieved in different cell systems suggests that factors other than the level of expression of the modulation target are responsible of such potentiation.
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PMID:Modulation of melphalan cytotoxic activity in human melanoma cell lines. 886 30

The antracyclines induce multiple intracellular effects; however, inhibition of the nuclear enzyme topoisomerase II (TOPO II) is the main mechanism of action. Resistance to anthracyclines in tumor cells is multifactorial. The main mechanisms are: (1) the classic multidrug resistance (MDR) phenotype, which is due to the presence of P-glycoprotein (PGP) in plasma membrane, that is, a "pump" that can extrude a wide range of anticancer drugs. Membrane-active drugs (e.g., verapamil) have been found in vitro to reverse this phenotype. Most clinical studies including chemosensitizers have, however, been disappointing. (2) Non-PGP-mediated MDR: this phenotype is characterized by expression of other proteins in the plasma membrane which are also able to extrude anticancer drugs. (3) Changes in the intracellular distribution of drug: this mechanism has been demonstrated in several cell lines, most often in combination with PGP or non-PGP-mediated resistance. (4) Glutathione transferases (GST) and detoxification mechanisms: these represent a multigene family of enzymes that conjugate glutathione to chemically reactive groups. Direct evidence for a causative role of GST in anthracycline resistance is missing. (5) Alterations in TOPO II (at-MDR): DNA topoisomerases are involved in several aspects of DNA metabolism, in particular genetic recombination, DNA transcription, and chromosome segregation. Low levels of expression or alterations in TOPO II are associated in vitro with resistance. (6) Increased DNA repair: in several cell lines, an increase in the efficacy of DNA repair has been associated with resistance to doxorubicin (DOX). So far, only classic MDR has been shown to contribute to resistance in clinical conditions, whereas evidence for the other mechanisms of resistance is still missing.
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PMID:Cellular resistance to anthracyclines. 891 38

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


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