Comparison of the mutagenicity of amsacrine with that of a new clinical analogue, CI-921.

The mutagenicity of CI-921, the 4-methyl-5-(N-methyl)carboxamide derivative of the clinical antileukaemia agent, amsacrine, has been assessed using both bacterial and mammalian cells. CI-921 is distinguished from amsacrine in its high activity against some experimental tumours and is currently undergoing phase I clinical trial. Like 9-aminoacridine and amsacrine, CI-921 is mutagenic to the Salmonella typhimurium frameshift tester strain TA1537, but shows no sign of inducing base pair changes in strain TA100. In Chinese hamster cell culture, however, it differs from 9-aminoacridine in causing extensive chromosomal aberrations and an increase in mutations at the hypoxanthine-guanine phosphoribosyltransferase locus. It induces the formation of tightly packed and multilayered colonies in treated cultures of C3H/10T1/2 cells, but its action differs from that of benzo[a]pyrene, which induces type III fibroblastic multilayered colonies. Side-by-side comparison of the mutagenic properties of CI-921 and amsacrine showed no substantial differences at similar toxicity, suggesting that the increased lipophilicity and DNA-binding affinity of CI-921, which are thought to contribute to its increased antitumour activity, do not concomitantly increase the efficiency of in vitro mutagenesis or cell transformation.