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Title: Effect of quinolones which target bacterial gyrase and topoisomerase IV on mammalian type II topoisomerases
Author: Rance, Holly Ashlene
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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uinolones are a family of drugs used to treat bacterial infections by targeting bacterial type II topoisomerases (TOP2s), DNA gyrase and topoisomerase IV. Recent studies have shown that quinolones can cause genotoxicity in mammalian cells. Genotoxicity occurs when an agent causes damage to the genetic apparatus of a cell. Due to the similarities between the mammalian and bacterial TOP2 enzymes it is thought that the quinolones are targeting mammalian TOP2 to produce their genotoxic response. The aim of this study was to investigate if quinolone genotoxicity involves mammalian TOP2. Using the micronucleus assay, the genotoxicity of two quinolones ciprofloxacin and gemifloxacin was tested in three Nalm-6 cell lines containing varying amounts of TOP2. With ciprofloxacin only the Nalm-6TOP2A+/- cells showed genotoxicity, whereas for gemifloxacin only the Nalm-6 WT cells showed genotoxicity, suggesting that for gemifloxacin the removal of TOP2A or TOP2B lowers the genotoxicity of the quinolone. A selection of quinolones were tested using the Trapped in AgaRose DNA ImmunoStaining (TARDIS) assay to determine whether they stabilise the TOP2-DNA complexes in mammalian cells as known TOP2 poisons do. The analysis showed that after three hours incubation the level of complexes increased, indicating that the quinolones are able to stabilise TOP2-DNA complexes. Taken together the micronucleus and TARDIS assay data show that the quinolones are targeting mammalian TOP2 at high concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available