Mutagenicity profiles of newer amsacrine analogues with activity against solid tumours: comparison of microbial and mammalian systems.
Amsacrine, an acridine derivative used clinically in the treatment of acute leukaemia, has formed the basis for the development of further compounds with high activity against experimental solid tumours, one of which is currently in clinical trial. We have compared the ability of these drugs to cause point mutations in bacteria, 'petite' mutations in yeast and mutations in mammalian cells. Several of the compounds are frameshift mutagens in Salmonella typhimurium TA1537 while some cause 'petite' mutagenesis in Saccharomyces cerevisiae. All are highly clastogenic and have significant mutagenic activity at the 6-thioguanine locus in cultured V79 Chinese hamster fibroblasts following 1 h drug exposures. None are mutagenic at the ouabain locus of these cells. The relationship between different indicators of mutagenicity has been studied using an additional set of amsacrine analogues, some of which are mutagenic in S. typhimurium TA98. There is a highly significant relationship between mutation frequency (measured as resistance to 6-thioguanine) and either cytotoxicity (D37 values in a clonogenic assay) or clastogenicity (ability to induce micronuclei). However, there is no correlation with mutagenicity in microbial systems. The results suggest that the cytotoxicity, clastogenicity and mutagenic activity of the amsacrine analogues is mediated by similar mechanisms, probably involving the enzyme DNA topoisomerase II.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
van Zijl
P
P
Baguley
B C
BC
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D005347:Fibroblasts / Q000187:drug effects; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects
D000677:Amsacrine