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)

Over the past decade, DNA topoisomerase I and II appeared to be the targets of some antitumor agents: CPT-11 and Topotecan derived from Camptothecin which interact with topoisomerase I; Actinomycin D, Adriamycin and Daunorubicin, Elliptinium Acetate, Mitoxantrone, Etoposide and Teniposide, Amsacrine which interact with topoisomerase II. The multiple functions of these enzymes are important as they play a role during replication, transcription, recombination, repair and chromatine organisation. Particularly, they relax torsional constraints which appear when intertwined DNA strands are separated while replication fork or RNA polymerases are moving. To some extent, topoisomerase I and II are structurally and functionally different. Moreover, topoisomerase I is not indispensable for a living cell whereas topoisomerase II is. Drug-topoisomerase interaction which probably leads to antitumoral effect of the compounds studied in this review is not a trivial inhibition of the enzyme but rather a poisoning due to stabilization of cleavable complexes between the enzyme and DNA. These stabilized complexes are likely to induce apoptosis-like programmed cell death, which is characterised by DNA fragmentation. However, it appears that it is the collision of the replication fork with the drug-stabilized cleavable complex that is responsible for the cytotoxicity of the drug: poisoning of topoisomerases by antitumor agents leads to a new concept of "dynamic toxicity". Although they interact with a common target, topoisomerase II poisons have differential effects on macromolecules syntheses, cell cycle and chromosome fragmentation; a few compounds may produce free radicals. Because of these differential effects in addition to quantitative and qualitative variations of stabilized cleavable complexes, in particular DNA sequences on which topoisomerase II is stabilized, these antitumor agents do not resemble each other. Cellular resistance to topoisomerases poisons results of two principal types of alteration: target and/or drug transport modification. Decreased ability to form the cleavable complex in resistant cells may be the consequence of both decreased amount of topoisomerase or altered enzyme. On the other hand, overexpression of membrane P-glycoprotein, which pumps drugs out of the cell by an energy dependent process provokes a decreased accumulation of these drugs. Cross resistances to other drugs are mainly under control of these two different mechanisms of resistance. A complete knowledge of their individual effects and mechanisms of resistance would allow a better clinical use of topoisomerases poisons, especially when administered in combination chemotherapy.
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PMID:[Poisons of DNA topoisomerases I and II]. 808 Oct 34

Quantitative and qualitative aspects of topoisomerase (Topo) I and II were studied in 17 malignant ovarian tumors [eight untreated and nine after platinum/cyclophosphamide (Pt/Cy) chemotherapy]. Median Topo II catalytic activity was lower (P < 0.05) in tumors after Pt/Cy chemotherapy in comparison to untreated tumors, while no differences were found for Topo I catalytic activity in tumors before and after chemotherapy, as was also found in a previous study (Van der Zee et al. Cancer Res., 51: 5915-5920, 1991). Teniposide (VM-26)-induced cleavable complex formation correlated (r = 0.60; P < 0.05) with Topo II activity, while Topo II decatenation activity was equally but incompletely inhibited by VM-26 in all tumors. No differences were found in Topo II cleavage site patterns in plasmid BR322 DNA for all tumors using an indirect end-labeling procedure. Cleavable complex formation of Topo I by camptothecin (Cpt) did not correlate with Topo I catalytic activity, while Topo I catalytic activity could equally and completely be inhibited by Cpt. By Western blotting, Topo II alpha protein expression was detected in four of eight untreated tumors and three of nine tumors after Pt/Cy chemotherapy, whereas in all tumors a M(r) 150,000 degradation product of Topo II beta was detected. Topo I protein was detected in all tumors at varying levels, but the protein levels did not correlate with Topo I catalytic activity or cleavable complex formation by Cpt. Our study shows that Topo I and II, isolated from human malignant tumors, can be stimulated by Cpt and VM-26, respectively, to induce DNA cleavage, which suggests that topoisomerases are real targets for chemotherapy in patients with ovarian cancer. From in vitro data from the literature it appears that the cleavable complex assay reflects both quantitative and qualitative changes as well as changes in the phosphorylation state of Topo I and II. In combination with the feasibility of the cleavable complex assay for Topo I and II in human malignant tumors, which was found in the present study, it appears that at present the determination of cleavable complex formation by tumors seems to be the most promising parameter of Topo I or II expression in human tumors to be related to response to Topo I- or II-targeted chemotherapy.
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PMID:Quantitative and qualitative aspects of topoisomerase I and II alpha and beta in untreated and platinum/cyclophosphamide treated malignant ovarian tumors. 830 37

Anticancer pharmacology offers rich prospects for future therapeutic design. Knowledge of antitumoral agents pharmacology have widely advanced: understanding of the molecular cytotoxic mechanism of available agents, discovery of new compounds with a different and no-interfering mechanism of action. Since ten years, the identification of a couple of nuclear enzyme, DNA-topoisomerases, has answered to this goal. These enzymes catalyse the topological changes of the double strand DNA, participating to vital processes of cell metabolism. These enzymes are now know to be the intracellular target of widely used cytotoxic agents (such as anthracycline, Etoposide, Teniposide for DNA topoisomerase II) and for two new compounds in clinical trials (irinotecan and topotecan, both analogues of camptothecin, for DNA-topoisomerase I). This two last molecules, currently in phase II development, are promising. They seem to be synergistic in combination with available anticancer agents, but this remains to be demonstrated. Other drugs, inhibiting both DNA-topoisomerases I and II, are yet investigating. Would they provide new answers for the future?
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PMID:[Topoisomerases: therapeutic value]. 870 94

Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic cytokine, CD95 ligand. Synergy was observed at concentrations of teniposide that were insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand did not modulate the formation or removal of such complexes after teniposide treatment. These processes were also unaffected by ectopic expression of bcl-2. Teniposide enhanced CD95 expression in a glioma cell line with wild-type p53 (LN-229) but not in two p53 mutant cell lines (T98G, LN-308). Forced expression of a transdominant negative p53 mutant prevented the teniposide induced augmentation of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand and teniposide. Teniposide did not alter CD95 ligand expression, and forced expression of CD95 did not modulate sensitivity to VM26. Thus, teniposide-induced DNA lesions and alterations in CD95 or CD95 ligand are not necessary for teniposide-induced sensitization of human malignant glioma cells to CD95-mediated apoptosis.
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PMID:Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression. 954 55

The distribution of VM-26 (Teniposide)-stabilized cleavable complexes within DNA loops bound to the nuclear matrix was determined to provide further insights into the mode of DNA synthesis inhibition by VM-26. Covalent binding of [(3)H]VM-26 was 9-fold greater per milligram of nuclear matrix protein compared with high salt-soluble nonmatrix protein of CEM cells. The ratio declined from 9-fold in CEM cells to 4-fold in drug-resistant VM-1/C2 cells, which have decreased nuclear matrix DNA topoisomerase IIalpha. VM-26 induced a concentration-dependent increase in the frequency of cleavable complex formation with actively replicating matrix DNA. At 25 microM VM-26, the frequency was 32 +/- 2 (SEM) complexes per 10(6) bp of replicating matrix DNA compared with 13 +/- 2 (SEM) complexes per 10(6) bp of nonreplicating DNA in the matrix fraction. VM-26 at concentrations as high as 25 microM stabilized less than 3 complexes per 10(6) bp in the various nonmatrix DNA domains, since the nonmatrix DNA comprises the DNA loop domains that are distal to the matrix-bound replication sites. A negligible frequency of cleavable complex formation was detected in both the matrix and nonmatrix DNA domains of drug-resistant VM-1/C2 cells. Compared with untreated control cells, VM-26 induced an accumulation of nascent DNA in the nuclear matrix fraction of CEM cells but decreased the amount of nascent DNA in the nonmatrix fraction. The extensive cleavable complex formation on matrix replicating DNA stalled most of the replication forks within 1 kb of the replication sites on the nuclear matrix. The results provide evidence that nascent DNA bound to the nuclear matrix is an important site of VM-26 cleavable complex formation, and that these complexes inhibit DNA synthesis by blocking the movement of nascent DNA away from replication sites on the nuclear matrix.
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PMID:Topoisomerase II cleavable complex formation within DNA loop domains. 1080 51

The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposide-induced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.
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PMID:Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells. 2143 63

The transcription factor MYB plays key roles in hematopoietic cells and has been implicated the development of leukemia. MYB has therefore emerged as an attractive target for drug development. Recent work has suggested that targeting MYB by small-molecule inhibitors is feasible and that inhibition of MYB has potential as a therapeutic approach against acute myeloid leukemia. To facilitate the identification of small-molecule MYB inhibitors we have re-designed and improved a previously established cell-based screening assay and have employed it to screen a natural product library for potential inhibitors. Our work shows that teniposide and etoposide, chemotherapeutic agents causing DNA-damage by inhibiting topoisomerase II, potently inhibit MYB activity and induce degradation of MYB in AML cell lines. MYB inhibition is suppressed by caffeine, suggesting that MYB is inhibited indirectly via DNA-damage signalling. Importantly, ectopic expression of an activated version of MYB in pro-myelocytic NB4 cells diminished the anti-proliferative effects of teniposide, suggesting that podophyllotoxins disrupt the proliferation of leukemia cells not simply by inducing general DNA-damage but that their anti-proliferative effects are boosted by inhibition of MYB. Teniposide and etoposide therefore act like double-edged swords that might be particularly effective to inhibit tumor cells with deregulated MYB.
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PMID:A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity. 3017 51

Objective- Vascular calcification is a major risk factor for rupture of atherosclerotic plaques. High expression of BMP2 (bone morphogenetic protein 2) in lesions suggests its importance in vascular calcification during atherosclerosis. Teniposide is a Topo II (DNA topoisomerase II) inhibitor and is used for cancer treatment. Previously, we reported that teniposide activated macrophage ABCA1 (ATP-binding cassette transporter A1) expression and free cholesterol efflux indicating Topo II inhibitors may demonstrate antiatherogenic properties. Herein, we investigated the effects of teniposide on the development of atherosclerosis and vascular calcification in apoE-/- (apoE deficient) mice. Approach and Results- apoE-/- mice were fed high-fat diet containing teniposide for 16 weeks, or prefed high-fat diet for 12 weeks followed by high-fat diet containing teniposide for 4 weeks. Atherosclerosis and vascular calcification were determined. Human aortic smooth muscle cells were used to determine the mechanisms for teniposide-inhibited vascular calcification. Teniposide reduced atherosclerotic lesions. It also substantially reduced vascular calcification without affecting bone structure. Mechanistically, teniposide reduced vascular calcification by inactivating BMP2/(pi-Smad1/5/8 [mothers against decapentaplegic homolog 1, 5, and 8])/RUNX2 (runt-related transcription factor 2) axis in a p53-dependent manner. Furthermore, activated miR-203-3p by teniposide functioned as a link between activated p53 expression and inhibited BMP2 expression in inhibition of calcification. Conclusions- Our study demonstrates that teniposide reduces vascular calcification by regulating p53-(miR-203-3p)-BMP2 signaling pathway, which contributes to the antiatherogenic properties of Topo II inhibitors.
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PMID:Inhibition of Vascular Calcification. 3035 14


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