Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

DNA topoisomerase-IIalpha (topo-IIalpha) is a target enzyme of adriamycin (ADM). Glutathione-S-transferase-pi is known to be correlated with the resistance of various anticancer drugs including mitomycin C (MMC) and ADM. Expression levels of topo-IIalpha and GST-pi mRNA of primary colorectal lesions were semi-quantitatively determined by the RT-PCR method in 22 patients with colorectal cancer, who underwent hepatic arterial infusion of ADM and MMC mixed with degradable starch microspheres for synchronous (n=17) or metachronous (n=5) liver metastasis. Expression of topo-IIalpha mRNA/beta-actin mRNA was 0.872+/-0.564 (mean+/-SD) in responders (PR, n=10) and 0.369+/-0.133 in non-responders (SD+PD, n=12) (p=0.047). The relative expression of GST-pi was 0.638+/-0.593 in responders and 1.014+/-0.682 in non-responders (p=0.22). These results suggest that determining the mRNA expression of topo-IIalpha is useful for predicting the efficacy for this regimen, whereas determining the mRNA expression of GST-pi is not.
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PMID:[Efficacy of hepatic arterial infusion of adriamycin and mitomycin C mixed with degradable starch microspheres for liver metastasis of colorectal cancer--correlation with the mRNA expression of DNA topoisomerase-IIalpha and glutathione-S transferase-pi in primary lesions]. 1555 21

To elucidate the sensitivity of adenocarcinoma of the lung to cisplatin and irinotecan, intracellular glutathione (GSH) and glutathione S-transferase (GST)-pi concentrations and topoisomerase (topo) I activity were investigated using six adenocarcinoma cell lines. The antiproliferative activity was determined by MTT assay in terms of inhibition concentration (IC50) values. The IC50 values to cisplatin were not correlated with the amounts of intracellular GSH or GST-pi, but with intracellular accumulation of platinum (r = -0.91, p = 0.013). IC50 values to SN-38 were correlated with topo I activity determined by relaxation assay of pBR322 (r = -0.83, p = 0.040). These results suggest that platinum accumulation and topo I activity have definite impacts on the sensitivity of lung adenocarcinoma to cisplatin and irinotecan, respectively.
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PMID:Determinants of cisplatin and irinotecan activities in human lung adenocarcinoma cells: evidence of cisplatin accumulation and topoisomerase I activity. 1599 39

The effect of low-dose nitric oxide (NO) on gamma-ray-induced micronucleus (MN) frequency was investigated in RAW264.7 cells. Treatment of RAW264.7 cells with 0.25 mM sodium nitroprusside (SNP), a chemical NO donor, reduced the frequency of micronuclei induced by 5 Gy gamma rays by 43 to 45% between 3 and 12 h post-treatment. This effect was blocked by carboxy-PTIO, suggesting that NO may play a role in the reduction of radiation-induced MN frequency. To examine possible mechanisms underlying this effect, we first looked at changes in the antioxidant system after SNP treatment. A significant increase in intracellular glutathione (GSH) was seen in SNP-treated cells between 3 and 12 h post-treatment. Depletion of GSH with buthionine sulfoximine (BSO) increased the gamma-ray-induced increase in MN frequency. Detailed studies using various inducers of intracellular GSH suggested that GSH induction has a partial role in the reducing effect of NO on the gamma-ray-induced MN frequency. Next, the effect of NO on DNA repair and replication systems was examined. Wortmannin, an inhibitor of DNA-dependent protein kinase (DNA-PK), dose-dependently inhibited the reducing effect of NO, while caffeine, an inhibitor of ATM kinase and ATR kinase, did not. DNA-PK activity was increased by NO treatment. Etoposide, a topoisomerase II inhibitor, dose-dependently blocked the effect of NO in reducing the gamma-ray-induced MN frequency. These results suggest that the mechanisms of the effect of NO on the gamma-ray-induced MN frequency include elevation of GSH and up-regulation of DNA-PK activity for repairing double-strand breaks. NO may act as a signal for repair systems, e.g. for nonhomologous recombination and for the replication system in S phase, to reduce the MN frequency.
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PMID:Effect of nitric oxide on gamma-ray-induced micronucleus frequency in RAW264.7 cells. 1629 78

Multidrug resistance (MDR) is a major obstacle to successful application of cancer chemotherapy and also a basic problem in cancer biology. Studies on the molecular basis of MDR have revealed that a number of proteins over express in multidrug resistant cells viz., multidrug resistant MDR1 gene product P-glycoprotein, the multidrug resistance-associated protein (MRP) and enzymes associated with the glutathione (GSH) metabolism. Decreased expression or altered activity of topoisomerase II has also been implicated in MDR. In the present investigation a number of changes in phase II detoxification parameters have been noticed in drug resistant cells but the novel aspect of the present report is the observation that the metal copper is involved in drug resistance. Although copper plays important roles in many human and other biological systems and even in the treatment of cancer but the relation of Cu and drug resistance has not so far been studied in detailed. The present report describes the novel findings that the level of copper increases with the development of drug resistance in Ehrlich ascites carcinoma and in Lewis lung carcinoma cells and also in serum of mice bearing drug resistant cancer cells compared to mice bearing drug sensitive cells; the work indicates the important aspect of treating drug resistant cancer patients by lowering Cu level in the cancerous cells and serum prior to treatment.
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PMID:The role of copper in development of drug resistance in murine carcinoma. 1678 40

The aim of this work was to determine the functional activities of four different antioxidative enzymes (glutathione reductase, glutathione-S-transferase, glutathione peroxidase, thioredoxin reductase) and the protein expression of three ATP-binding cassette transporters (P-glycoprotein, multidrug resistance protein 1, multidrug resistance protein 2) in a panel of 14 human cancer cell lines. Enzyme activities and transporter expression were then correlated with the in-vitro cytotoxic activities (GI50 values) of 19 standard antitumor drugs. Analogous data from the National Cancer Institute were used for comparison. The GI50 values of the platinum complexes, alkylating agents, antimetabolites, topoisomerase inhibitors and antimitotic drugs were determined by crystal violet or 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay. Standard enzymatic assays employed to measure the glutathione peroxidase, glutathione-S-transferase, glutathione reductase and thioredoxin reductase activities. The protein expression of the ATP-binding cassette transporter proteins was investigated by the Western-blot method. The delta method was used to normalize the data before bivariant correlation analysis. Only a few correlations between enzyme and cytotoxic activities of the antitumor agents were found. The GI50 values for melphalan and camptothecin correlated positively with the activity of glutathione-S-transferase, whereas GI50 values for methotrexate correlated positively with the cellular activities of both glutathione reductase and thioredoxin reductase. A significant correlation between glutathione reductase and thioredoxin reductase activities was found in our panel of cell lines. Neither P-glycoprotein nor multidrug resistance protein 2 expression could be detected by Western blot analysis in any cell lines investigated, but multidrug resistance protein 1 was consistently observed in all but four lines. Multidrug resistance protein 1 expression correlates positively with the GI50 values of several drugs, e.g. vinblastine and etoposide, and negatively with the GI50 values of 5-fluorouracil. The results confirm the complexity of resistance to antitumor agents and show that the GSH-thioredoxin system alone is not a good indication of intrinsic resistance for many of these anticancer drugs.
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PMID:Correlations between the activities of 19 standard anticancer agents, antioxidative enzyme activities and the expression of ATP-binding cassette transporters: comparison with the National Cancer Institute data. 1735 91

Thimerosal is an organic mercury compound that is widely used as a preservative in vaccines and other solution formulations. The use of thimerosal has caused concern about its ability to cause neurological abnormalities due to mercury accumulation during a normal schedule of childhood vaccinations. While the chemistry and the biological effects of methylmercury have been well-studied, those of thimerosal have not. Thimerosal reacted rapidly with cysteine, GSH, human serum albumin, and single-stranded DNA to form ethylmercury adducts that were detectable by mass spectrometry. These results indicated that thimerosal would be quickly metabolized in vivo because of its reactions with protein and nonprotein thiols. Thimerosal also potently inhibited the decatenation activity of DNA topoisomerase II alpha, likely through reaction with critical free cysteine thiol groups. Thimerosal, however, did not act as a topoisomerase II poison and the lack of cross-resistance with a K562 cell line with a decreased level of topoisomerase II alpha (K/VP.5 cells) suggested that inhibition of topoisomerase II alpha was not a significant mechanism for the inhibition of cell growth. Depletion of intracellular GSH with buthionine sulfoximine treatment greatly increased the K562 cell growth inhibitory effects of thimerosal, which showed that intracellular glutathione had a major role in protecting cells from thimerosal. Pretreatment of thimerosal with glutathione did not, however, change its K562 cell growth inhibitory effects, a result consistent with the rapid exchange of the ethylmercury adduct among various thiol-containing cellular reactants. Thimerosal-induced single and double strand breaks in K562 cells were consistent with a rapid induction of apoptosis. In conclusion, these studies have elucidated some of the chemistry and biological activities of the interaction of thimerosal with topoisomerase II alpha and protein and nonprotein thiols and with DNA.
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PMID:Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of DNA topoisomerase II alpha. 1819 31

A novel cyclolignanic quinone, 7-acetyl-3',4'-didemethoxy-3',4'-dioxopodophyllotoxin (CLQ), inhibits topoisomerase II (TOPO II) activity. The extent of this inhibition was greater than that produced by the etoposide quinone (EQ) or etoposide. Glutathione (GSH) reduces EQ and CLQ to their corresponding semiquinones under anaerobic conditions. The latter were detected by EPR spectroscopy in the presence of MgCl(2) but not in its absence. Semiquinone EPR spectra change with quinone/GSH mol ratio, suggesting covalent binding of GSH to the quinones. Quinone-GSH covalent adducts were isolated and identified by ESI-MS. These orthoquinones also react with nucleophilic groups from BSA to bind covalently under anaerobic conditions. BSA thiol consumption and covalent binding by these quinones are enhanced by MgCl(2). Complex formation between the parent quinones and Mg(+2) was also observed. Density functional calculations predict the observed blue-shifts in the absorption spectra peaks and large decreases in the partial negative charge of electrophilic carbons at the quinone ring when the quinones are complexed to Mg(+2). These observations suggest a possible role of Mg(+2) chelation by these quinones in increasing TOPO II thiol and/or amino/imino reactivity with these orthoquinones.
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PMID:Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation. 1832 25

Glutathione (GSH), as the major small-molecule antioxidant in cells, has been implicated in the regulation of cell proliferation and apoptosis. Salvicine (SAL), a novel diterpenoid quinone compound, exhibits potent antitumor activities both in vitro and in vivo by poisoning topoisomerase II (Topo II) and has entered Phase II clinical trials for cancer therapy. Herein, we provide further evidence that SAL-induced DNA double-strand breaks (DSBs) and apoptosis by GSH depletion drives H2O2 generation and Topo II inhibition. Our data reveal that treatment with SAL results in a pronounced increase in intracellular H2O2 and is accompanied by the occurrence of DNA DSBs and apoptosis in epithelial HeLa cells. Furthermore, SAL was also noted to trigger a dramatic depletion of intracellular GSH via its direct reaction with GSH. Importantly, the introduction of GSH and overexpression of catalase antagonized SAL-mediated DNA DSBs and apoptosis, and the GSH synthesis inhibitor dl-buthionine-[S,R]-sulfoximine reduced SAL-mediated H2O2 generation, indicating that SAL-mediated H2O2 generation is derived from intracellular GSH depletion. Notably, SAL-mediated Topo II inhibition was also concentration-dependently reversed by GSH. Furthermore, we found that Topo II-defective HL-60/MX2 cells were almost completely resistant to SAL-induced DNA DSBs, suggesting that, in addition to its direct inhibitory effect on Topo II, SAL-mediated H2O2 generation may also trigger DNA DSBs via poisoning of Topo II. All these findings together suggest that GSH-depletion-driven H2O2 generation and Topo II inhibition are both critical for SAL-induced DNA DSBs and apoptosis.
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PMID:Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition. 1858 59

Goniothalamin (GTN) isolated from Goniothalamus sp. has been demonstrated to induce apoptosis in a variety of cancer cell lines including Jurkat T leukemia cells. However, the mechanism of GTN-induced apoptosis upstream of mitochondria is still poorly defined. In this study, GTN caused a decrease in GSH with an elevation of reactive oxygen species as early as 30 min and DNA damage as assessed by Comet assay. Analysis using topoisomerase II processing of supercoiled pBR 322 DNA showed that GTN caused DNA damage via a topoisomerase II-independent pathway suggesting that cellular oxidative stress may contribute to genotoxicity. A 12-fold increase of caspase-2 activity was observed in GTN-treated Jurkat cells after 4h treatment and this was confirmed using Western blotting. Although the caspase-2 inhibitor Z-VDVAD-FMK inhibited the proteolytic activity of caspase-2, apoptosis ensued confirming that caspase-2 activity was not crucial for GTN-induced apoptosis. However, GTN-induced apoptosis was completely abrogated by N-acetylcysteine further confirming the role of oxidative stress. Since cytochrome c release was observed as early as 1h without any appreciable change in Bcl-2 protein expression, we further investigated whether overexpression of Bcl-2 confers resistance in GTN-induced cytotoxicity. Using a panel of Jurkat Bcl-2 transfectants, GTN cytotoxicity was not abrogated in these cells. In conclusion, GTN induces DNA damage and oxidative stress resulting in apoptosis which is independent of both caspase-2 and Bcl-2.
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PMID:Goniothalamin-induced oxidative stress, DNA damage and apoptosis via caspase-2 independent and Bcl-2 independent pathways in Jurkat T-cells. 2002 95

A major limitation of cancer chemotherapy is development of resistance. In this study, we analyzed KB-3-1 cells and adriamycin-selected multidrug resistant sublines KB-A1 and KB-A10 cells for mechanisms of resistance. KB-A10 cells are 10-fold more resistant than KB-A1 cells but have lower P-glycoprotein. Of the known mechanisms of multidrug resistance, topoisomerase II and lung-resistance-related protein were altered between the resistant cell lines. Glutathione-S-transferase activity and multidrug-resistance-related protein levels were higher in the resistant cell lines compared to the sensitive cells but were similar in KB-A1 and KB-A10 cells. Results indicate differential regulation of mechanisms of resistance with stepwise selection.
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PMID:Differential mechanisms of multidrug resistance are expressed during stepwise selection of KB-3-1 cells with adriamycin. 2152


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