Genotoxicity of topoisomerase II inhibitors: an anti-infective perspective.
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.
Smart
Daniel J
DJ
Genetic Toxicology, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire SG12 0DP, UK. daniel.j.smart@gsk.com
D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000633:toxicity; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D024841:Fluoroquinolones / Q000494:pharmacology / Q000633:toxicity; D006657:Histones / Q000032:analysis / Q000378:metabolism; D006801:Humans; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D059005:Topoisomerase II Inhibitors
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C468783:H2AX protein, human; D006657:Histones; D009153:Mutagens; D059005:Topoisomerase II Inhibitors