Genotoxicity of topoisomerase II inhibitors: an anti-infective perspective

Toxicology. 2008 Dec 30;254(3):192-8. doi: 10.1016/j.tox.2008.08.023. Epub 2008 Sep 18.


At present, an inevitable consequence of a chemical's inhibitory activity on key regulators of DNA topology in bacteria, the type II topoisomerases, is a less pronounced effect on their eukaryotic counterparts. In the context of anti-infectives drug development, this may pose a risk to patient safety as inhibition of eukaryotic type II topoisomerases (TOPO II) can result in the generation of DNA double-strand breaks (DSBs), which have the potential to manifest as mutations, chromosome breakage or cell death. The biological effects of several TOPO II inhibitors in mammalian cells are described herein; their modulation of DSB damage response parameters is examined and evidence for the existence of a threshold concept for genotoxicity and its relevance in safety assessment is discussed. The potential utility of gammaH2AX, a promising and highly sensitive molecular marker for DSBs, in a novel genotoxicity 'pre-screen' to conventional assays is also highlighted.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-Infective Agents / pharmacology*
  • Anti-Infective Agents / toxicity
  • DNA Breaks, Double-Stranded / drug effects*
  • Fluoroquinolones / pharmacology
  • Fluoroquinolones / toxicity
  • Histones / analysis
  • Histones / metabolism
  • Humans
  • Mutagenicity Tests
  • Mutagens / pharmacology
  • Mutagens / toxicity
  • Phosphorylation / drug effects
  • Topoisomerase II Inhibitors*


  • Anti-Infective Agents
  • Fluoroquinolones
  • H2AX protein, human
  • Histones
  • Mutagens
  • Topoisomerase II Inhibitors