Genetic toxicology of tricyclic carboxamides, a new class of DNA binding antitumour agent.
(N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (acridine carboxamide; NSC 601316) is an acridine-derived experimental antitumour agent with curative properties against Lewis lung carcinoma in mice. Although it intercalates into DNA and also appears to interact with topoisomerase II, its DNA binding properties appear distinct from other acridine derivatives such as the clinical antitumour drug, amsacrine. The mutagenic properties of acridine carboxamide, together with three related compounds containing either 9-aminoacridine or phenazine chromophores, were studied at the 6-thioguanine and ouabain loci in cultured V79 Chinese hamster fibroblasts. Each compound, when tested at concentrations causing up to 90% kill, had weak but significant activity at the 6-thioguanine but not at the ouabain locus. All drugs were potent inducers of micronuclei, indicating high clastogenic activity. There was a highly significant relationship between mutation frequency (as resistance to 6-thioguanine) and either cytotoxicity (measured as D37 in a clastogenicity assay) or clastogenicity. A broader range of compounds was also tested for microbial mutagenicity. In Salmonella typhimurium strains, none were mutagenic in TA98, TA100 or TA102 but several were mutagenic in TA1537, a frameshift tester strain. Some drugs also caused 'petite' mutagenesis in Saccharomyces cerevisiae. In general, compounds with the phenazine chromophore, which has no positive charge, were the most mutagenic in these systems. However, activity was not related to mammalian mutagenicity or antitumour effect. The results suggest that in mammalian cells, the cytotoxicity, clastogenicity and mutagenic activity of these drugs are mediated by similar mechanisms to those for amsacrine analogues, probably involving the enzyme DNA topoisomerase II.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Hill
C M
CM
Baguley
B C
BC
D000166:Acridines / Q000633:toxicity; D000609:Aminoacridines / Q000633:toxicity*; D000677:Amsacrine / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens; D010619:Phenazines / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; D009153:Mutagens; D010619:Phenazines; D000677:Amsacrine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D004247:DNA