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)

Studies have suggested that recombinant tumor necrosis factor-alpha (TNF-alpha) may potentiate the killing of murine tumor cells by drugs targeted at DNA topoisomerase II. We have examined the combined cytotoxic effects of the topoisomerase-targeted drug etoposide and TNF in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines using clonogenic assays and a novel flow cytometry technique relying on differential uptake of fluorescein diacetate (FDA) and propidium iodide (PI) by viable and nonviable cells. Good correlation of IC50 determinations for etoposide were noted between clonogenic assays and the FDA/PI technique for both classic and variant SCLC cell lines. The effects of etoposide on the classic SCLC line H209 were potentiated by TNF with a decrease in the IC50 from 3.3 microM to 1.0 microM as determined by FDA/PI. Tumor necrosis factor alone had little effect on the growth or cloning efficiency of H209 cells. Tumor necrosis factor alone stimulated the growth and cloning of variant SCLC line N417, but the cytotoxicity of etoposide was not potentiated by TNF in N417 cells. Tumor necrosis factor alone inhibited the growth and cloning of the NSCLC line H125 but exerted a marked protective effect against higher concentrations of etoposide. It appears that the interaction of TNF with etoposide varies between cell lines and between subclasses of human lung cancer.
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PMID:Interaction of recombinant human tumor necrosis factor and etoposide in human lung cancer cell lines. 217 61

DNA topoisomerase II has been implicated in regulating chromosome interactions. We investigated the effects of the specific DNA topoisomerase II inhibitor, teniposide on nuclear events during oocyte maturation, fertilization, and early embryonic development of fertilized Spisula solidissima oocytes using DNA fluorescence. Teniposide treatment before fertilization not only inhibited chromosome separation during meiosis, but also blocked chromosome condensation during mitosis; however, sperm nuclear decondensation was unaffected. Chromosome separation was selectively blocked in oocytes treated with teniposide during either meiotic metaphase I or II indicating that topoisomerase II activity may be required during oocyte maturation. Teniposide treatment during meiosis also disrupted mitotic chromosome condensation. Chromosome separation during anaphase was unaffected in embryos treated with teniposide when the chromosomes were already condensed in metaphase of either first or second mitosis; however, chromosome condensation during the next mitosis was blocked. When interphase two- and four-cell embryos were exposed to topoisomerase II inhibitor, the subsequent mitosis proceeded normally in that the chromosomes condensed, separated, and decondensed; in contrast, chromosome condensation of the next mitosis was blocked. These observations suggest that in Spisula oocytes, topoisomerase II activity is required for chromosome separation during meiosis and condensation during mitosis, but is not involved in decondensation of the sperm nucleus, maternal chromosomes, and somatic chromatin.
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PMID:Teniposide, a topoisomerase II inhibitor, prevents chromosome condensation and separation but not decondensation in fertilized surf clam (Spisula solidissima) oocytes. 217 57

The cytotoxicity anti-tumour intercalating agents such as the anthraquinone mitoxantrone is thought to relate to DNA binding and the trapping of DNA topoisomerase II complexes on cellular DNA. We have studied the uptake, nuclear location, DNA binding mode and DNA damaging capacity of mitoxantrone in a small cell lung carcinoma cell line (NCI-H69) compared with an in vitro-derived variant subline (NCI-H69/LX4) that exhibits "classical" multi-drug resistance (MDR). Variant cells maintained under doxorubicin selection showed reduced RNA levels that returned to control values within 7 days of growth under non-selective conditions. Variant cells released from selection stress showed resistance to DNA cleavage by doxorubicin, mitoxantrone, 4'-epidoxorubicin, 4'-deoxy-doxorubicin but reduced resistance to aclacinomycin A and a 9-alkyl substituted anthracycline in broad agreement with the cross-resistance patterns for cytotoxicity. Mitoxantrone treated NCI-H69 cells were found to accumulate DNA-protein crosslinks during a 4 hr post-treatment incubation period whereas variant cells maintained depressed levels of crosslinking. There was no apparent abnormality in the availability or drug sensitivity of topoisomerase II assayed in crude nuclear extracts of NCI-H69/LX4 cells. Whole cell uptake of radiolabelled mitoxantrone was depressed (50%) in NCI-H69/LX4 compared with NCI-H69, whereas assessment of nuclear-bound drug in individual cells by a fluorescence quenching technique showed at least a 10-fold greater level of target protection. The quenching results provide evidence of a high affinity, saturable mode of drug binding, favoured at low drug concentrations, that correlated with DNA cleavage capacity. We propose that the cytotoxic action of mitoxantrone is dependent upon a restricted and persistent form of binding to DNA that favours the long-term or progressive trapping of topoisomerase II complexes.
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PMID:Mitoxantrone-DNA binding and the induction of topoisomerase II associated DNA damage in multi-drug resistant small cell lung cancer cells. 217

Numerous antitumor and antibacterial agents inhibit type II DNA topoisomerases, yielding, in each case, a complex of enzyme covalently bound to cleaved DNA. We are investigating the mechanism of inhibitor action by using the type II DNA topoisomerase of bacteriophage T4 as a model. The T4 topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli. Two m-AMSA-resistant phage strains were previously isolated, one with a point mutation in topoisomerase subunit gene 39 and the other with a point mutation in topoisomerase subunit gene 52. We report here that the wild-type T4 topoisomerase is inhibited by six additional antitumor agents that also inhibit the mammalian type II topoisomerase: ellipticine, 9-OH-ellipticine, 2-me-9-OH-ellipticinium acetate, mitoxantrone diacetate, teniposide, and etoposide. Further, one or both of the m-AMSA-resistance mutations alters the enzyme sensitivity to each of these agents, conferring either cross-resistance or enhanced sensitivity. Finally, the gene 39 mutation confers on T4 topoisomerase a DNA gyrase-like sensitivity to the gyrase inhibitor oxolinic acid, thus establishing a direct link between the mechanism of action of the anti-bacterial quinolones and that of the antitumor agents. These results strongly suggest that diverse inhibitors of type II topoisomerases share a common binding site and a common mechanism of action, both of which are apparently conserved in the evolution of the type II DNA topoisomerases. Alterations in DNA cleavage site specificity caused by either the inhibitors or the m-AMSA-resistance mutations favor the proposal that the inhibitor binding site is composed of both protein and DNA.
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PMID:Evidence for a common mechanism of action for antitumor and antibacterial agents that inhibit type II DNA topoisomerases. 217 9

To study the biochemical processes which DNA topoisomerase II carries out in mammalian cells, which have not been identified, we have examined the effects on chromosome replication in Chinese hamster ovary cells of an agent which traps molecules of topoisomerase II when they are covalently integrated into DNA during their reaction. This agent, 4'-demethylepipodophyllotoxin 9-(4,6-O-thenylidene-beta-D-glucopyranoside) (VM-26), targets this enzyme specifically according to a compelling body of evidence. Using synchronously growing cells, we found that VM-26 at a cytotoxic concentration (0.08 microM) did not affect DNA replication during the S phase. The formation of mitotic chromosomes was delayed by 4 h, and its rate was reduced thereafter, causing a delay in mitosis of greater than 14 h in 65% of the cells; in some cells, the chromatin was aberrantly condensed, forming diffuse chromosomes or particles. Chromosome formation was completely inhibited at 0.32 microM VM-26. DNA fragments derived from topoisomerase II molecules covalently integrated in DNA and trapped by VM-26 were detected by FIGE analysis in the G2 period, but not during the S phase. The delay of chromosome formation appeared to be caused by two factors: first, a delay in the completion of DNA replication, because progress of some cells to mitosis after removal of VM-26 was prevented by aphidicolin, an inhibitor of DNA polymerases alpha and delta; and second, a delay of chromosome formation in cells which had apparently completed DNA replication. The observations reported here show that topoisomerase II carries out reactions which are essential for formation of mitotic chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DNA topoisomerase II is required for formation of mitotic chromosomes in Chinese hamster ovary cells: studies using the inhibitor 4'-demethylepipodophyllotoxin 9-(4,6-O-thenylidene-beta-D-glucopyranoside). 217 48

Novobiocin affects DNA metabolism in both prokaryotes and eukaryotes, resulting in cell death. In prokaryotes, the drug is a specific inhibitor of DNA gyrase, a type II topoisomerase that can be purified on a novobiocin-Sepharose column. The yeast type II topoisomerase is neither the biochemical, nor the genetic target of the antibiotic. We have purified the major yeast novobiocin binding proteins and identified one of them as the beta-subunit of the yeast mitochondrial F1 ATP synthetase, a protein highly conserved throughout evolution. The inactivation of this protein might explain the toxic effects of novobiocin on higher eukaryotic cells.
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PMID:The F1 ATP synthetase beta-subunit: a major yeast novobiocin binding protein. 217 64

Interaction between tumor necrosis factor (TNF) and the DNA topoisomerase II inhibitor, etoposide VP-16, in cell killing has been studied. To accurately investigate the nature of DNA damage during the cell killing process, experiments were assessed using the highly TNF-sensitive WEHI164.13 murine fibrosarcoma clone and DNA filter elution methodology. Concomitant treatment of cells with combination of TNF/VP-16 resulted in marked enhancement of cell lysis. Using the alkaline elution technique, we show that TNF fails to induce DNA single-strand breaks as compared to those generated by VP-16. In addition, the potentiating effect of VP-16 on TNF-mediated WEHI164.13 cell killing was not associated with an increase in its intrinsic activity with respect to DNA single-strand break formation. While the 2 phospholipase A2 inhibitors, quinacrine and dexamethasone, were efficient in inhibiting TNF-mediated cell lysis, only quinacrine was efficient in selectively abrogating the TNF/VP-16 cell killing pathway. The inhibitory effect of quinacrine on VP-16/TNF-mediated cell lysis was accompanied by a marked decrease in VP-16-mediated DNA single-strand break generation. Taken together, our findings suggest that TNF and TNF/VP-16 treatments may involve different events during cell killing and support the hypothesis that 2 signals are required for optimal induction of cell lysis by the combination of VP-16/TNF: one signal provided by VP-16 resulting in topoisomerase II inhibition and subsequent DNA single-strand break generation, and a second signal involving TNF.
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PMID:Potentiation of TNF-mediated cell killing by VP-16: relationship to DNA single-strand break formation. 224 91

Recombinant human tumor necrosis factor (rHTNF) alone had no effect on L929 tumor cells at 100 units/ml for 20 h of continuous exposure. However, under the same conditions, rHTNF markedly enhanced the cytotoxicity of Adriamycin, actinomycin D, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, teniposide (VM 26), and etoposide (VP 16), all targeted at DNA topoisomerase II. The rHTNF had a minimally enhancing effect on the cytotoxicity of bleomycin, hydroxyurea, and 1-beta-D-arabinofuranosylcytosine and no effect on the cytotoxicity of cis-platinum, mitomycin C, vincristine, and vinblastine, all chemotherapeutic drugs with dose-related cytotoxic effects on L929 cells but mechanisms of action which do not appear to involve topoisomerase II. Treatment with rHTNF first and then topoisomerase-targeted drugs yielded no enhanced cytotoxicity, whereas pretreatment with drug followed by rHTNF yielded marked enhancement of cytotoxicity. Topoisomerases have previously been implicated in cell kill phenomena following treatment with certain chemotherapeutic agents [K.M. Tewey, et al., Science (Wash. DC), 226:466-468, 1984]. The data suggest that the lethality to the cell from topoisomerase-targeted drug treatment is increased by rHTNF in vitro. We suggest that rHTNF may be a useful adjuvant to this class of drugs which has well-known antitumor activity.
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PMID:Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II. 243 63

We have provided evidence recently for a defect in DNA topoisomerase II in ataxia--telangiectasia (A-T) lymphoblastoid cells. This study was initiated to investigate in greater detail the nature of this defect. Southern hybridization analysis was carried out on DNA from control and A-T Epstein--Barr virus-transformed lymphoblastoid cells. The pattern of digestion, using several restriction enzymes, was the same in both cell types. Expression of topoisomerase II mRNA occurred to the same extent and there was no difference in the size of mRNA between the cell types. Western blot analysis revealed that the same amount of a major band of topoisomerase II protein was present in A-T and control cells but there was evidence for a reduced amount of a lower-molecular-weight form in A-T only. Extraction and purification did not lead to alteration in size of the enzyme or in amount recovered.
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PMID:Study of DNA topoisomerase II in ataxia-telangiectasia cells. 247 31

In order to characterize more fully the mechanism by which casein kinase II is regulated in mammalian cells, the effect of epidermal growth factor (EGF) on the activity of the kinase in human A-431 carcinoma cells was examined. Treatment of cells with EGF prior to lysis consistently resulted in a transient 4-fold increase in the activity of cytosolic casein kinase II. Activity rose sharply between 20 and 30 min, peaked at approximately 50 min, and returned to basal levels by approximately 120 min. Similar results were obtained using the casein kinase II specific peptide substrate, Arg-Arg-Arg-Glu-Glu-Glu-Thr-Glu-Glu-Glu, or DNA topoisomerase II (which is specifically modified by the kinase in vivo and serves as a high affinity substrate in vitro) as the phosphate acceptor in assays. Identification of casein kinase II as the stimulated activity was confirmed by partial proteolytic mapping and phosphoamino acid analysis of modified topoisomerase II, by inhibition at nanomolar levels of heparin or micromolar levels of nonradioactive GTP, and by the ability to employ radioactive GTP as a direct phosphate donor. The EGF stimulation of casein kinase II was dependent on the availability of intracellular (but not extracellular) calcium. In addition, hormonal action was modulated by calcium/phospholipid-dependent protein kinase (protein kinase C). Casein kinase II stimulation did not require an increase in the concentration of the kinase, protein synthesis, the continual presence of a small effector molecule, or a direct interaction with the EGF receptor/tyrosine kinase. In contrast, hormonal activation of the kinase was dependent on the phosphorylation of casein kinase II or a terminal stimulatory factor.
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PMID:Regulation of casein kinase II activity by epidermal growth factor in human A-431 carcinoma cells. 247 67


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