Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bacterial gyrase inhibitors, ciprofloxacin and PD 124816, were tested for clastogenic and aneugenic activity in V79 Chinese hamster lung cells in vitro. Cells were exposed for 3 h, washed free of drug, and subcultured for assessment of various endpoints. For structural chromosomal aberration (SCA) analysis, cells were incubated for 18 h, and treated with Colcemid for 2 h before harvest. For micronucleus (MN) analysis, treated cells were incubated with cytochalasin B (CYB) for 16 h. Aneugenicity was assessed by utilizing antikinetochore antibody to detect kinetochore-containing (K +) MN. Both quinolones induced significant increases in SCAs and MN, indicating clastogenic activity. With both compounds, however, the MN response was apparent at lower doses, and remained much higher throughout the dose range than the SCA response. The induced MN were predominantly K --, indicating that aneugenicity was not playing a major role in their induction. A possible explanation for the chromosome effects is that cross-reactivity of the gyrase inhibitors with mammalian topoisomerase II interferes with the separation of chromatids at anaphase leading to chromosome breaks and MN. Quinolones are known to inhibit resolution of the normally transient topoisomerase II-DNA cleavable complex, which may result in chromosome stickness. Thus, SCAs detected in metaphase cells may be attributed to quinolone-induced inhibition of topoisomerase II prior to mitosis while MN arise in binucleated cells as a result of this effect which interferes with chromatid separation during anaphase.
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PMID:In vitro induction of micronuclei and chromosome aberrations by quinolones: possible mechanisms. 867 3

Diplochromosomes, consisting of four chromatids lying side-by-side, instead of the normal two, are produced when cells go through two rounds of DNA replication without separation of chromatids. They are thus an indication of the failure of the normal chromosome separation mechanism. In the present experiments, induction of diplochromosomes by inhibitors of topoisomerase II (Topo II) was used to provide further evidence that Topo II is required for separation of daughter chromosomes. Actively growing cultures of CHO cells were treated with Colcemid, and separated into metaphase and interphase fractions, each of which was treated for 2 h with the Topo II inhibitor being tested. The cells were then cultivated in fresh medium without inhibitor for periods of between 18 and 44 h, and metaphase cells once again accumulated by treatment with Colcemid. Chromosome preparations were made in the standard way and stained with Giemsa. Up to 2,000 metaphases were counted from each culture, and the proportion with diplochromosomes calculated. At appropriate concentrations, the Topo II inhibitors etoposide and mitoxantrone induced substantial levels of metaphases with diplochromosomes in cultures that had been treated when the cells were in interphase (up to 30% and 11%, respectively). Amsacrine, however, only produced a smaller proportion (4.7%) of metaphases with diplochromosomes after a much longer culture period following treatment. All the inhibitors caused severe chromosome damage. When used to treat metaphase cells, mitoxantrone and amsacrine only induced diplochromosomes after prolonged culture, although a small number of diplochromosomes were seen after etoposide treatment and a shorter period of culture. Results with cells treated in metaphase might indicate that Topo II is, in fact, not required for anaphase chromosome separation, although it is clearly important for segregation of newly replicated DNA.
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PMID:Induction of diplochromosomes in mammalian cells by inhibitors of topoisomerase II. 991 81