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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Teniposide is the result of extensive, long-term efforts to refine and improve on the cytotoxic activity of naturally occurring compounds extracted from podophyllin resins and purified. Isolation of an extremely potent though minor component of one of the early podophyllin derivatives led in turn to the synthesis and evaluation of several aldehyde condensation products. Two of these, teniposide and etoposide, were further investigated when their considerable antitumor activity in animals became apparent. Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. As a result of elevated enzyme levels or enzyme activity, or both, in transformed cells, topoisomerase II inhibitors are highly selective for cancer cells versus normal cells. Although teniposide is not substantially more potent than etoposide in terms of catalytic inhibition or stabilization of the DNA-enzyme intermediate, it is more readily taken up by cells, which results in greater teniposide accumulation within the cells and, thus, a greater capacity for cytotoxicity.
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PMID:Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16). 132 25

The epipodophyllotoxins, etoposide and teniposide, have been used in leukemias and malignant lymphomas for the past 15 years. Although etoposide has acquired a place in many first-line protocols for lymphomas and, more recently, for leukemias, the role of teniposide has remained limited. Teniposide is a more potent inhibitor of topoisomerase II than etoposide, and has a less toxic effect on hematopoietic progenitor cells. Both drugs have been regarded as equitoxic and cross-resistant. The role of teniposide in front-line treatment of leukemias has only been established in childhood acute lymphoblastic leukemia (ALL). Some promising results have been obtained in small numbers of patients with refractory adult ALL and acute monoblastic leukemia. However, the remission rates and remission duration were not significantly different from those of other combination regimens. Data on teniposide in untreated acute nonlymphoblastic leukemia are very scarce. In non-Hodgkin's lymphoma, the antineoplastic activity of teniposide has been demonstrated in studies by the European Organization for Research and Treatment of Cancer and in two large studies conducted by the Australian and New Zealand Lymphoma Co-operative Chemotherapy Study Group. In these studies, teniposide had comparable but not significantly better activity than vincristine. The dose-dependent antineoplastic activity of teniposide has led to its use in several conditioning regimens in bone marrow transplantation for leukemias and lymphomas. The limited clinical data currently available on teniposide seem to warrant further clinical trials with this agent in leukemias and lymphomas.
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PMID:Teniposide in lymphomas and leukemias. 141 40

Teniposide [4'-demethylepipophyllotoxin-4-(4,6-O-thenylidene-beta-D- glucopyranoside) (VM-26)] is a cancer chemotherapeutic drug with a high target specificity for DNA topoisomerase II. This agent induces repairable protein-bridged double-strand DNA breaks, which have been correlated with cytotoxicity, but high concentrations of VM-26 also induce irreversible DNA degradation and apoptotic cell death. It is not known whether this degradation occurs uniformly throughout the genome or in a gene-specific manner. To answer this question, DNA was isolated from HL-60 promyelocytic leukemia cells exposed to 5 microM VM-26 for varying periods of up to 12 h. Nucleosomal "ladders" on 2.0% agarose gels stained with ethidium bromide were detectable after 3 h of exposure, indicative of apoptosis. Gene-specific DNA degradation was investigated by Southern blot analysis. The genes for 18S rRNA and glucose-6-phosphate dehydrogenase were representatives of constitutively expressed (i.e., "housekeeping") genes. The proto-oncogenes c-myc, c-Ha-ras, and bcl-2 were examined as examples of other transcriptionally active genes, while transcriptionally inactive genes in HL-60 cells were studied by probing for the immunoglobulin heavy chain joining region and lambda light chain constant region genes. The rates of DNA degradation, and its extent after 12 h, were similar for all nuclear genes studied. However, there was striking resistance of mitochondrial DNA to endonucleolytic degradation. These data demonstrate that VM-26 can elicit a widespread degradative process which affects nuclear but not mitochondrial DNA.
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PMID:Teniposide induces nuclear but not mitochondrial DNA degradation. 159 97

The data presented confirm the possibility of enzymatic formation of discrete DNA-fragments appearing during fractionation of nuclear DNA by FIGE. Teniposide-dependent pattern of DNA-fragments as well as occurrence of protein-linked DNA breaks suggest that discrete cleavage of intact nuclear DNA is modulated by DNA topoisomerase II. The possible relationship between discrete DNA-fragments and the higher order chromatin folding are discussed.
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PMID:[Fractionation of eukaryotic DNA in a pulsed electrical field. II. Discrete DNA fragments and level of structural organization of chromatin]. 181 95

We found that 4'-demethylepipodophyllotoxinthenylidene-beta-D-glucoside (VM-26; Teniposide), which specifically inhibits the enzyme DNA topoisomerase II, induces the formation of quadriradial chromosomes in Chinese hamster ovary cells. VM-26 traps topoisomerase II molecules when they are covalently integrated into DNA during their reaction. Quadriradial chromosomes are formed by reciprocal exchange of double-stranded DNA between single chromatids of two different chromosomes. Using synchronised cells, we found that they were formed after a single replication cycle in the presence of VM-26 at a low concentration (0.008 micro M), which does not affect DNA replication, and occurred in 50% of the mitotic cells at a concentration of 0.16 micro M. They were also formed when VM-26 was present for only 1.5 h before mitosis, after the completion of S-phase DNA replication. Chromatids bearing a translocated segment of another chromatid, which were derived from recombined chromosomes, were observed in late metaphase cells. Segregation of the daughter genomes was defective in many mitotic cells, probably because chromatids with two or no centromeres and kinetochores, formed from chromosomes recombined between their centromeres, could not be segregated. In the light of evidence that topoisomerase II molecules covalently integrated in DNA are trapped and therefore more abundant in the presence of VM-26, and that this enzyme can effect recombination of double-stranded DNA in vitro, we interpret these observations as evidence that topoisomerase II can mediate chromosome recombination in vivo.
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PMID:Chromosome recombination and defective genome segregation induced in Chinese hamster cells by the topoisomerase II inhibitor VM-26. 184 68

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

A well defined extrachromosomal DNA element, referred to as an episome (Ostrowski, M., Richard-Foy, H., Wolford, R., Berard, D., and Hager, G. (1983) Mol. Cell. Biol. 3, 2045-2057), was employed as a target for the topoisomerase II inhibitors amsacrine and teniposide. Both drugs have distinct mechanisms of action in cleaving the episome, as defined by topological forms conversion assays. The concentration ranges required to measure episomal cleavage are similar. The onset of damage induced by amsacrine begins within 1 min and is maintained at that level for at least 1 h. Teniposide induces damage that peaks between 30 and 60 min. The amsacrine-induced damage is only partially reversible, whereas teniposide-induced damage is almost completely reversible. Sites of specific cleavage are quite dissimilar. Multiple cleavage sites are formed in the episomal regulatory regions after amsacrine treatment, whereas a single cleavage in the regulatory region and one outside this region are found after teniposide treatment. Transcriptional activation using dexamethasone does not change the amount or site preference of episomal cleavage induced by either agent. Damage to the episome was quantitatively compared with damage produced in genomic DNA between 500 and 24,000 rad equivalents. The study showed that amsacrine has a significant (33-38-fold) preference for episomal DNA over genomic DNA.
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PMID:A study of drug-induced topoisomerase II-mediated DNA lesions on episomal chromatin. 255 Apr 34

The p170 and p180 forms of topoisomerase II have been compared. The concentration dependence of ATP for catalytic activity of the two forms of the enzyme was identical, and each was equally sensitive to novobiocin. Orthovanadate was found to be a potent inhibitor of catalytic activity of both p170 and p180, with an IC50 value of about 2 microM for each. Under standard reaction conditions, relaxation of supercoiled pBR322 by p180 was highly processive, while p170 performed the same reaction in a distributive manner. The optimal concentration of KCl for catalytic activity of p180 was 20-30 mM higher than that for p170. Comparison of their thermal stability showed that p180 was inactivated at twice the rate of p170. Teniposide and merbarone selectively inhibited catalytic activity of p170, requiring concentrations 3-fold and 8-fold lower, respectively, than those required for equivalent inhibition of p180. Similar selectivity for p170 was seen for teniposide-stimulated DNA cleavage or its inhibition by merbarone. Analysis of sites of DNA cleavage indicated a subset of sites that were either preferred or unique for each of the enzymes. A synthetic oligonucleotide representative of p170 sites selectively inhibited the p170 enzyme. Immunoblotting of p170 and p180 from U937 cells at different stages of proliferation showed that p170 levels declined as the cells reached the plateau phase of growth, while p180 levels were low during rapid proliferation and increased as the growth rate slowed. The data indicate that the p170 and p180 forms of topoisomerase II can be distinguished biochemically, pharmacologically, and by differential cellular regulation.
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PMID:Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II. 255 97

DNA topoisomerases have been proposed to function in a variety of genetic processes in both prokaryotes and eukaryotes. Here, we have assessed the role of DNA topoisomerase II in mammalian DNA replication by determining the proximity of newly synthesized DNA to covalent enzyme-DNA complexes generated by treating cultured rat prostatic adenocarcinoma cells with teniposide. Teniposide (VM-26), an epipodophyllotoxin, is known to interact with mammalian DNA topoisomerase II so as to trap the enzyme in a covalent complex with DNA. We have found that the teniposide-induced trapping of such complexes requires MgCl2, is stimulated by ATP and is inhibited by novobiocin. The formation of covalent complexes seems to be reversible on removal of teniposide. Furthermore, analysis of the covalent complexes formed between 3H-thymidine pulse-labelled DNA and topoisomerase II following teniposide treatment reveals a direct association of the enzyme with nascent DNA fragments. Our results suggest that DNA topoisomerase II may interact with newly replicated daughter DNA molecules near DNA replication forks in mammalian cells.
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PMID:Newly replicated DNA is associated with DNA topoisomerase II in cultured rat prostatic adenocarcinoma cells. 301 53

Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are increasingly used in cancer medicine. Teniposide is more highly protein-bound than etoposide, and its uptake and binding to cells is also greater. Etoposide and teniposide are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell cycle. They appear to act by causing breaks in DNA via an interaction with DNA topoisomerase II or by the formation of free radicals. Teniposide is more potent as regards the production of DNA damage and cytotoxicity. Most studies show a biexponential decay following intravenous administration of etoposide and teniposide. The terminal elimination half-life of etoposide is less than that of teniposide, and the plasma and renal clearances of etoposide are greater. The peak plasma concentrations of drug and the area under the concentration versus time curve are linearly related to the intravenous dose of both drugs. Considerable interpatient variability of pharmacokinetic parameters exists following intravenous etoposide and teniposide. Various metabolites of etoposide and teniposide have been identified but their detection and quantitation are disputed. Approximately 30 to 70% of a dose of etoposide is accounted for by excretion, whereas the figure appears to be only 5 to 20% for teniposide. The bioavailability of oral etoposide is about 50% but its absorption is not linear with increasing dose within the range in clinical use. There is considerable inter- and intrapatient variability in the pharmacokinetics of oral etoposide. There is no evidence of accumulation of etoposide and teniposide after multiple consecutive doses by the intravenous or oral routes. The exact roles of the liver and kidney in metabolism and excretion of etoposide and teniposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This together with the phase-specific action of etoposide and teniposide and their increasingly widespread use in cancer medicine make the clinical pharmacology of these drugs of great clinical importance.
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PMID:The clinical pharmacology of etoposide and teniposide. 329 62


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