Anaerobic incubation and mutagenicity of nitracrine analogues in Salmonella typhimurium.
Nitracrine [1-nitro-9-(dimethylaminopropylamino)-acridine] is a clinical antitumour agent with hypoxia-selective cytotoxicity and radiosensitizing activity. Developments in tumour therapy using either nitracrine itself or some of its analogues under development are likely to be targeted at anaerobic regions of tumours. We have investigated the effects of anaerobiosis on mutagenic activity of nitracrine and a small series of analogues in three derivatives of Salmonella typhimurium frameshift strain hisC3076. Nitracrine-induced mutagenicity was apparently enhanced by a period of anaerobic incubation followed by an aerobic period, with maximal mutagenic effectiveness (as revertants/nmol) being seen at 24 h anaerobiosis. However, the maximal number of nitracrine-induced revertants was not increased by anaerobic incubation, and the relationship between mutagenicity and toxicity remained similar. Comparisons of the effects of anaerobiosis on mutagenicity of bacterial strains with different DNA repair capacities suggested that anaerobiosis was not simply depressing 'SOS' repair. Comparisons of nitracrine with four of its analogues showed that this effect was not a universal characteristic of either acridine derivatives or of nitracrine analogues. Rather, the dose displacements obtained paralleled hypoxic cell selective cytotoxicity in mammalian cells. If this result extends to other compounds, experiments of this nature using the bacterial strains could provide a novel and useful screening system to identify hypoxia-selective cytotoxic anticancer drugs of potential clinical value.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Roberton
A M
AM
Turner
P M
PM
D000609:Aminoacridines / Q000494:pharmacology*; D000693:Anaerobiosis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D009564:Nitracrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000609:Aminoacridines; D000970:Antineoplastic Agents; D009153:Mutagens; D009574:Nitro Compounds; D009564:Nitracrine