Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ataxia telangiectasia (AT) cell lines are characterised by their hypersensitivity to ionizing radiation and bleomycin, and their failure to inhibit DNA synthesis after DNA damage. A recent report [Singh et al. (1988) Nucl. Acids Res. 16, 3919-3929] indicated that a reduction in topoisomerase II (topo II) activity was a feature of AT lymphoblast cell lines. We have studied the possible role of DNA topoisomerases in determining the phenotype of an AT fibroblast cell line. AT5BIVA cells are sensitive to the topo II inhibitors etoposide (VP16) and amsacrine (m-AMSA), compared to normal human fibroblasts (MRC5-V1 and VA13). AT5BIVA cells express a 3-fold higher level of topo II protein than MRC5-V1 cells, and 6-fold higher than VA13. This is reflected in elevated topo II activity in AT5BIVA cells. Untransformed AT5BI cells also show elevated topo II activity compared to untransformed normal cells. The extent of overproduction of topo II in AT5BIVA cells is comparable with that seen in a mutant Chinese hamster cell line, ADR-1, which is similarly hypersensitive to both bleomycin and topo II inhibitors. However, ADR-1 cells show neither hypersensitivity to ionizing radiation nor abnormal inhibition of DNA synthesis following DNA damage. Topo II overproduction per se does not appear sufficient to generate an "AT-like" phenotype. AT5BIVA cells express a reduced level of topoisomerase I (topo I) and are hypersensitive to the topo I inhibitor, camptothecin. ADR-1 cells express a normal level of topo I, indicating that a reduction in the level of topo I is not the inevitable consequence of an elevation in topo II.
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PMID:Overproduction of topoisomerase II in an ataxia telangiectasia fibroblast cell line: comparison with a topoisomerase II-overproducing hamster cell mutant. 253 56

We have isolated two Chinese hamster ovary cell lines, designated ADR-4 and ADR-5, which exhibit hypersensitivity to intercalating agents and epipodophyllotoxins. These drugs are thought to exert their cytotoxicity via an interaction with the enzyme topoisomerase II. However, there is no apparent change in the level or catalytic activity of topoisomerase II in the mutant cells. Drug sensitivity does not appear to be due to increased drug transport because accumulation of radiolabeled actinomycin D is similar in mutant and wild-type cells. Both mutant cell lines show enhanced resistance to hydrogen peroxide and to organic peroxides. ADR-4 cells show a degree of temperature sensitivity. ADR-5 cells show mild sensitivity to UV irradiation. Neither cell line shows significant sensitivity to mono- or bifunctional alkylating agents, ionizing radiation, or bleomycin. Cell fusion studies indicate that the phenotype of each mutant cell line is recessive and that the mutants represent two different genetic complementation groups. These studies also indicate that ADR-4 and ADR-5 Adriamycin-sensitive mutant, ADR-1. These results indicate that sensitivity to topoisomerase II inhibitors can result from abnormalities in several genes. These drug-sensitive mutants may be useful for studying the mechanisms of cell killing by topoisomerase II inhibitors, free radicals, and heat.
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PMID:Isolation of two Chinese hamster ovary cell mutants hypersensitive to topoisomerase II inhibitors and cross-resistant to peroxides. 254 43

Chronic lymphocytic leukemia is a neoplastic disease in which drug resistance invariably occurs. We have studied the uptake and interaction with molecular targets of two drugs, chlorambucil and adriamycin, in CLL lymphocytes and CHO cell lines. Resistance does not appear related to uptake for either drug. Exposure to CLB causes DNA cross-links in the sensitive but not in the resistant cell line. The GSH content of B-CLL lymphocytes is depleted after a 20-hr incubation. An inability to maintain its GSH content may contribute to this cell's vulnerability to CLB. The resistance of CLL lymphocytes to ADR may be related to the undetectable levels of its target enzyme DNA topoisomerase II. Future approaches may involve study of novel anthracyclines, DNA topoisomerase I inhibitors and the development of in vitro predictive tests.
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PMID:Studies on drug resistance in chronic lymphocytic leukemia. 256 Dec 48

We have investigated the biochemical basis for the hypersensitivity to intercalating agents and epipodophyllotoxins of a Chinese hamster cell mutant, ADR-1. More topoisomerase II-induced DNA strand breaks are accumulated by ADR-1 than by parental CHO-K1 cells following exposure to the intercalating agent amsacrine. Levels of induced DNA strand breaks correlate with cell killing. Topoisomerase II activity is elevated in ADR-1 cells as a consequence of an increased cellular level of topoisomerase II protein. We have studied the phenotype of cell hybrids generated by fusing parental and mutant cells. The hybrid ADR-1/CHO-K1 exhibits normal levels of resistance to amsacrine and expresses the lower, parental level of topoisomerase II. These results provide additional evidence that topoisomerase II mediates the cytotoxic action of intercalating agents and epipodophyllotoxins and suggest that the intracellular level of topoisomerase II is an important determinant of cellular sensitivity to these drugs. This has implications for antitumor therapy. ADR-1 cells provide a model system for studying the effects of topoisomerase II overproduction on cell proliferation and chromosome organization.
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PMID:Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. 284 76

We have shown that a mutant derivative of Chinese hamster ovary CHO-K1 cells, ADR-5, which shows hypersensitivity to topoisomerase II (topo II)-inhibitory drugs, is cross-sensitive to the site-selective cyclic AMP analogue 8-chloro-cyclic AMP. We tested the hypothesis that overexpression of the type I alpha regulatory subunit of protein kinase A may represent a common element conferring hypersensitivity to both topo II inhibitors and 8-chloro-cyclic AMP in ADR-5 cells. We have demonstrated that ADR-5 cells overexpress RI alpha protein, compared to parental CHO-K1 cells. Moreover, retroviral vector-mediated transfer of the RI alpha gene into CHO-K1 cells was able to confer a drug-hypersensitive phenotype similar to that exhibited by ADR-5 cells. Analysis of topo II protein levels and activity revealed no differences between parental and infected cells, suggesting that protein kinase A may be involved in the downstream processing of topo II-mediated events.
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PMID:Overexpression of the RI alpha subunit of protein kinase A confers hypersensitivity to topoisomerase II inhibitors and 8-chloro-cyclic adenosine 3'5'-monophosphate in Chinese hamster ovary cells. 751 50

Doxorubicin, ellipticine and etoposide are antineoplastic drugs with topoisomerase II inhibitory activity. The relationship between drug-induced sister-chromatid exchanges (SCEs) or chromosomal aberrations (CAs) and cytotoxicity, or drug-induced DNA double-strand breaks (DSBs) and cytotoxicity, or drug-induced SCEs and DSBs was investigated in human ovarian cancer cells sensitive (A2780) and resistant (A2780-DX3) to topoisomerase II inhibitors. 30-min drug treatments produced SCEs, CAs and DSBs in sensitive cells, doxorubicin being more potent than etoposide at equimolar concentrations. The same treatments of resistant (A2780-DX3) cells did not produce chromosomal damage (SCEs, CAs, DSBs) and no cytotoxicity was observed. A plot of cytotoxicity versus SCEs indicated a good correlation between these two parameters for topoisomerase II inhibitors and not for mytomicin C. The plot of DSBs versus SCEs also showed a very good correlation.
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PMID:Sister-chromatid exchanges, chromosomal aberrations and cytotoxicity produced by topoisomerase II-targeted drugs in sensitive (A2780) and resistant (A2780-DX3) human ovarian cancer cells: correlations with the formation of DNA double-strand breaks. 752 71

A series of twelve structurally related bisdioxopiperazines that included ICRF-187 (dexrazoxane), ICRF-159 (razoxane), ICRF-193, and ICRF-154 were examined both for their ability to inhibit the growth of Chinese hamster ovary (CHO) cells and their ability to inhibit the catalytic activity of mammalian DNA topoisomerase II. The bisdioxopiperazines exhibited a wide range in both growth inhibitory effects (30,000-fold), and in their ability to inhibit the catalytic activity of topoisomerase II (150-fold). The cytotoxicity of the bisdioxopiperazines toward CHO cells was highly correlated (correlation coefficient r = 0.86, P = 0.0003) with their inhibition of the catalytic activity of DNA topoisomerase II. This result strongly suggests that DNA topoisomerase II is the functional target of the bisdioxopiperazines. The stereoisomers (+)-ICRF-187 and (-)-ICRF-186 were observed to be equally cytotoxic and equally inhibitory toward DNA topoisomerase II. This result indicates that the bisdioxopiperazine binding site on DNA topoisomerase II is large enough or flexible enough to accommodate either form of the drug. The strongly metal-ion binding fully rings-opened hydrolysis product of ICRF-187, ADR-925, demonstrated no measurable inhibitory activity toward DNA topoisomerase II or cytotoxicity toward CHO cells.
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PMID:A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). 757 79

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

A2780 human ovarian cancer cell line and its multidrug resistant counterpart A2780-DX3 were utilized for this in vitro study. A2780-DX3 is resistant in various degrees to several topoisomerase II inhibitors but sensitive to vinca alkaloids. Simultaneous treatment of the A2780-DX3 line with 1000 U/mL rHuTNF largely reverses resistance to most topoisomerase II inhibitors. By itself, 1000 U/mL rHuTNF is not toxic to the resistant line. Uptake and retention of [3H]-Mitoxantrone are not modified by rHuTNF, whereas rHuTNF is very active in potentiating the effects of Mitoxantrone. After treatment with topoisomerase II inhibitors, Doxorubicin, Mitoxantrone, or VP16, rHuTNF restores DNA-SSB and DNA-protein cross-links in the resistant line to the level of the wild type. The cleavage activity of topoisomerase II in the resistant line is about 40% of the level present in the parental line. Five minutes after the addition of 1000 U/mL of rHuTNF, the cleavage activity in the resistant line is about 85% of the level present in the parental line. The catalytic activity of topoisomerase II is only 15% lower in the resistant line, but it is increased by about 50% 5 min after the addition of rHuTNF to the resistant line. These effects are transient and cannot be observed after 30 min. These transient direct effects of rHuTNF on topoisomerase II could be associated with its ability to restore sensitivity to inhibitors of topoisomerase II in the A2780-DX3 line.
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PMID:Reversal of "atypical"-multidrug resistance by recombinant human tumor necrosis factor in the human ovarian cancer cell line A2780-DX3. 801 63

N417/AMSA cells, about 80-fold resistant to mAMSA [4'-(9-acridinylamino)-methanesulfon-m-anisidide], were obtained by serial passages of the parental human small cell lung carcinoma NCI-N417 (N417/p) in stepwise drug concentrations. The N417/AMSA cells were found to be 114-, 100-, and 9-fold cross-resistant to the topoisomerase II (Topo II) inhibitors VM26, VP16 and Doxorubicin (DXR); they showed a 2-fold decrease in Topo II activity. Interestingly, N417/AMSA cells which exhibited a 3-fold increase in topoisomerase I (Topo I) activity were 28-fold cross-resistant to camptothecin (CPT), a specific inhibitor of Topo I. In order to investigate the cellular mechanisms leading to the development of resistance, the effects of mAMSA and CPT on parental and resistant cell lines were analysed by alkaline elution. A decrease in DNA single-strand breaks (DNA-SSB) was observed in N417/AMSA cells treated with mAMSA or CPT compared to parental cells. Similar differences were obtained in isolated nuclei, suggesting that no modification of mAMSA and CPT accumulation occurred in resistant cells. Topo I was purified from N417/p (Topo I/p) and N417/AMSA (Topo I/AMSA) cells in the exponential phase of growth, and the inhibitory effects of CPT on relaxation activities were determined. Topo I/AMSA was found to be about 7-fold less sensitive to CPT than Topo I/p, suggesting the possible involvement of a mutation outside the gene region sequenced (codons 420 to 642) or post-translational modifications of the Topo I enzyme. These data indicate that increased Topo I activity cannot be related to CPT resistance, and suggest that mAMSA can generate multiple cellular modifications which may be involved in resistance to various drugs.
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PMID:A human small cell lung carcinoma cell line, resistant to 4'-(9-acridinylamino)-methanesulfon-m-anisidide and cross-resistant to camptothecin with a high level of topoisomerase I. 809 10


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