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)

Forty-eight human squamous cell lung carcinomas of previously untreated patients were analyzed for resistance to doxorubicin and for the presence of topoisomerase II (Topo II), metallothionein (MT), thymidylate synthase (TS) and catalase (Cat). Significant correlations exist between resistance to doxorubicin measured by the in vitro short-term test and overexpression of MT and TS measured by immunohistochemistry. No significant correlation was found between resistance and expression of Topo II or Cat. No significant interrelationship between smoking habits of patients and expression of Topo II, MT, TS or Cat was found.
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PMID:Expression of topoisomerase II, catalase, metallothionein and thymidylate-synthase in human squamous cell lung carcinomas and their correlation with doxorubicin resistance and with patients' smoking habits. 133 Mar 47

We have isolated, following one-step mutagenesis, a Chinese hamster ovary cell mutant hypersensitive to the intercalating agent, adriamycin (4-fold compared to parental CHO-K1 cells). This agent exerts at least part of its cytotoxic action via inhibition of the nuclear enzyme, topoisomerase II. The mutant, designated ADR-3, showed hypersensitivity to all classes of topoisomerase II inhibitors, including actinomycin D, amsacrine (m-AMSA), etoposide (VP16) and mitoxantrone. ADR-3 cells also showed cross-sensitivity to ionizing radiation, but not to UV light. Cellular accumulation of radiolabeled actinomycin D was similar in parental and mutant cells. At equimolar doses, adriamycin induced more protein-associated DNA single- and double-strand breaks in ADR-3 cells than in CHO-K1 cells. Topoisomerase II activity was elevated to a small but significant degree in ADR-3 cells, and this was reflected in a 1.5-fold higher level of topoisomerase II protein in ADR-3 than in CHO-K1 cells, as judged by Western blotting. ADR-3 cells were hypersensitive to cumene hydroperoxide but cross-resistant to hydrogen peroxide, suggesting possible abnormality in the detoxification of peroxides by glutathione peroxidase or catalase. Glutathione peroxidase activity against hydrogen peroxide was similar in CHO-K1 and ADR-3 cell extracts, but activity against cumene hydroperoxide was evaluated to a small but significant extent in mutant cells. Catalase levels were not significantly different in ADR-3 and CHO-K1 cells. ADR-3 cells were recessive in hybrids with parental CHO-K1 cells with respect to sensitivity to topoisomerase II inhibitors and X-rays, and represent a different genetic complementation group from the previously reported adriamycin-sensitive mutant, ADR-1 [Davies et al., J. Biol. Chem., 263 (1988) 17724-17729].
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PMID:Isolation and partial characterisation of a mammalian cell mutant hypersensitive to topoisomerase II inhibitors and X-rays. 215 84

The aim of the study was to prove whether or not an association exists between the heat shock protein 70 (hsp70) and drug resistance. Tumor samples of 90 patients with previously untreated non-small lung carcinomas were investigated immunohistochemically for expression of resistance related proteins. Additionally, resistance to doxorubicin was determined using a short term test. No association between resistance related proteins. Additionally, resistance to doxorubicin was determined using a short term test. No association between resistance to doxorubicin and hsp70 was found. Of 63 resistant tumors, 33 showed low and 30 high hsp70 expression. Of the 26 sensitive tumors, 11 had low and 16 had high hsp70 expression. No relationship could be found between P-glycoprotein which is related to multidrug resistance and hsp70 expression or between hsp70 expression and expression of topoisomerase II, thymidylate synthase and metallothionein. On the other hand, a trend was noted for tumors with high glutathione S-transferase-pi expression to show high hsp70 expression. In addition, there was a significant relationship between hsp70 and catalase positivity. These data indicate that heat shock and stress promote intracellular oxidative damage and catalase is necessary for protection.
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PMID:Heat shock (hsp70) and resistance proteins in non-small cell lung carcinomas. 765 30

This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6-fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC subline was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5-FU and topoisomerase II inhibitors; and (2) cross-resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT-diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT-diaphorase inhibitor dicumarol on the wild-type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti-oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC-induced DNA interstrand cross-linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.
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PMID:Characterization of a human bladder cancer cell line selected for resistance to mitomycin C. 807 54

Human NK cells (with CD3-/56+ phenotype) acquired features characteristic of apoptosis after incubation with autologous monocytes, as revealed by apoptotic nuclear morphology, degradation of DNA into oligonucleosomal fragments, and reduced nuclear interchalation of propidium iodide. In contrast, T cells (CD3+/56-) remained non-apoptotic. The monocyte-induced apoptosis in NK cells was prevented by catalase, a scavenger of hydrogen peroxide; whereas superoxide dismutase (a scavenger of superoxide anion), hydroxyl radical scavengers such as mannitol and deferoxamine, or the hypochlorus acid scavenger taurine did not prevent apoptosis. Sodium azide, a myeloperoxidase inhibitor, substantially reduced the monocyte-induced apoptosis in NK cells. Exogenous hydrogen peroxide, at concentrations exceeding 1 microns, induced apoptosis in both NK and T cells. Apoptosis induced by hydrogen peroxide occurred independently of synthesis of protein or mRNA and was blocked by the endonuclease inhibitor aurin tricarboxylic acid. Furthermore, oxidatively induced apoptosis in NK cells was inhibited by herbimycin A, indicating that apoptosis was dependent on protein kinases. Two to five times more hydrogen peroxide was required to induce apoptosis in T cells compared with NK cells. Similarly, NK cells were considerably more susceptible to apoptosis induced by the topoisomerase II inhibitor etoposide or by gamma-irradiation than were T cells. We conclude that monocyte-derived reactive oxygen metabolites kill NK cells by apoptosis and that NK cells are unusually sensitive to oxidatively as well as non-oxidatively induced apoptosis.
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PMID:Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. 859 91

We have established a cisplatin resistant subline, MKN/CDDP, from the MKN-45 human stomach adenocarcinoma cell line. MKN/CDDP was 10.7 fold more resistant to cisplatin, 5.4 fold resistant to carboplatin, 2.7 fold resistant to 5-fluorouracil and only 1.4 fold resistant to adriamycin. To investigate the mechanism of the cisplatin resistance in the MKN/CDDP subline, we performed the biochemical characterization of MKN-45 and MKN/CDDP. MKN/CDDP cells showed no induction in p-glycoprotein and topoisomerase II. The level of glutathione S-transferase-pi was higher in MKN/CDDP than the parent line, but a similar level of glutathione S-transferase-L isoform was observed. Superoxide dismutase activity was 1.67 fold higher in the MKN/CDDP subline than the parent line, but 60 kDa catalase was much lower in the MKN/CDDP subline. In addition to those changes. MKN/CDDP was not able to attach to the culture dish, which is probably due to the lack of fibronectin association on the cell surface. The MKN/CDDP subline revealed a variety of biochemical changes which are related to drug inactivation and to cell substratum adhesion. The significance of each modification in the development of the cisplatin resistance will be evaluated in future studies.
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PMID:Biochemical characterization of cisplatin-resistance in MKN-45 human stomach adenocarcinoma cell line. 891 23

Contact-inhibited catalase-deficient fibroblast cell strain has been established from the homozygous hypocatalasemic C3H/Csb mutant mouse. This cell strain has low level of catalase enzyme activity and has normal level of enzyme activities of both glutathione peroxidase and superoxide dismutase. Catalase-deficient C3H/Csb mutant cell strain is markedly more sensitive to the toxicity of hydrogen peroxide compared to wild-type C3H/Csa cell strain. In addition, mutant cell strain is sensitive to X-rays and near-UV compared to wild-type cell strain, but shows the same sensitivities to topoisomerase II inhibitors, adriamycin and 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA), and the DNA cross-linking agents, cisdiamminedichloroplatinum (II) (cis-Pt) and trans-diamminedichloroplatinum (II) (trans-Pt). These cell strains will be of use in the study of the roles which catalase plays in the intracellular prevention of DNA damage induced by oxidative stress.
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PMID:Establishment and characterization of a hypocatalasemic mouse cell strain. 986 65

Caspase activation may occur in a direct fashion as a result of CD95 death receptor crosslinking (exogenous pathway) or may be triggered indirectly, via a Bcl-2 inhibitable mitochondrial permeabilization event (endogenous pathway). Thymocyte apoptosis is generally accompanied by proteasome activation. If death is induced by DNA damage, inactivation of p53, overexpression of a Bcl-2 transgene, inhibition of protein synthesis, and antioxidants (N-acetylcyteine, catalase) prevent proteasome activation. Glucocorticoid-induced proteasome activation follows a similar pattern of inhibition except for p53. Caspase inhibition fails to affect proteasome activation induced by topoisomerase inhibition or glucocorticoid receptor ligation. In contrast, caspase activation (but not p53 knockout or Bcl-2 overexpression) does interfere with proteasome activation induced by CD95. Specific inhibition of proteasomes with lactacystin or MG123 blocks caspase activation at a pre-mitochondrial level if thymocyte apoptosis is induced by DNA damage or glucocorticoids. In strict contrast, proteasome inhibition has no inhibitory effect on the mitochondrial and nuclear phases of apoptosis induced via CD95. Thus, proteasome activation is a critical event of thymocyte apoptosis stimulated via the endogenous pathway yet dispensable for CD95-triggered death.
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PMID:Proteasome activation as a critical event of thymocyte apoptosis. 1077 21

The quinobenzoxazines, a group of structural analogues of the antibacterial fluoroquinolones, are topoisomerase II inhibitors that have demonstrated promising anticancer activity in mice. It has been proposed that the quinobenzoxazines form a 2:2 drug-Mg(2+) self-assembly complex on DNA. The quinobenzoxazine (S)-A-62176 is photochemically unstable and undergoes a DNA-accelerated photochemical reaction to afford a highly fluorescent photoproduct. Here we report that the irradiation of both supercoiled DNA and DNA oligonucleotides in the presence of (S)-A-62176 results in photochemical cleavage of the DNA. The (S)-A-62176-mediated DNA photocleavage reaction requires Mg(2+). Photochemical cleavage of supercoiled DNA by (S)-A-62176 is much more efficient that the DNA photocleavage reactions of the fluoroquinolones norfloxacin, ciprofloxacin, and enoxacin. The photocleavage of supercoiled DNA by (S)-A-62176 is unaffected by the presence of SOD, catalase, or other reactive oxygen scavengers, but is inhibited by deoxygenation. The photochemical cleavage of supercoiled DNA is also inhibited by 1 mM KI. Photochemical cleavage of DNA oligonucleotides by (S)-A-62176 occurs most extensively at DNA sites bound by drug, as determined by DNase I footprinting, and especially at certain G and T residues. The nature of the DNA photoproducts, and inhibition studies, indicate that the photocleavage reaction occurs by a free radical mechanism initiated by abstraction of the 4'- and 1'-hydrogens from the DNA minor groove. These results lend further support for the proposed DNA binding model for the quinobenzoxazine 2:2 drug-Mg(2+) complex and serve to define the position of this complex on the minor groove of DNA.
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PMID:Efficient, Mg(2+)-dependent photochemical DNA cleavage by the antitumor quinobenzoxazine (S)-A-62176. 1095 13

The main objective of this study to analyze which of 31 cellular factors (resistance proteins, proliferative factors, apoptotic factors, angiogenic factors, proto-oncogenes) most accurately predict the resistance of non-small cell lung carcinomas. To this purpose, we used a short-term in vitro test that measures changes in the rate at which radioactive nucleic acid precursors are incorporated into tumor cells after the addition of doxorubicin to determine the response to doxorubicin in 94 non-small cell lung carcinomas. The results obtained by the short-term test were related to the various cellular factors which were in turn determined by immunohistochemistry and flow cytometry. A significant correlation was found between the data obtained by the short-term test and the expression of P-glycoprotein 170 (P = 0.00004), glutathione-S-transferase-pi (P = 0.0002), metallothionein (P = 0.0008), thymidylate synthase (P = 0.002), O6-methylguanine-DNA-methyltransferase (P = 0.008) and lung resistance-related protein (LRP, P = 0.03). There was only a weak correlation between heat shock proteins (HSP70) and no correlation between the expression of topoisomerase II or catalase and the short-term test results. To measure the proliferative activity, the following were determined: PCNA, cyclin A, cyclin D and cdk2. Only a weak relationship was found between the expression of cdk2 (P = 0.04) and PCNA (P = 0.05) and the doxorubicin response in vitro. Of the investigated pro-apoptotic factors (Fas/CD95, Fas ligand, caspase-3), only Fas/CD95 is significantly associated with the drug response (P = 0.007). The apoptotic index also reveals a significant correlation (P = 0.03). Angiogenesis, as measured by the microvessel density and the angiogenic factors, is inversely correlated to the resistance of non-small cell lung cancer. Platelet-derived endothelial cell growth factor (PD-ECGF) and vascular endothelial growth factor (VEGF) exhibit a significant relationship to the drug resistance (P = 0.0006 and P = 0.004, respectively). Of the investigated proto-oncogenes (Fos, Jun, ErbB-1, ErbB-2, Myc, Ras), only ErbB-2 is weakly associated with the in vitro short term test. In order to determine whether combining factors can result in improved predictive information, combinations of the factors (pairs, triplets) were analyzed. The systematic investigation of these combinations yields an improvement in the predictive information. With one factor up to 76.6% of the tumors, with two factors up to 85.4% and with three factors up to 89.5% of the tumors could be correctly diagnosed.
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PMID:Cellular predictive factors for the drug response of lung cancer. 1113 47


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