Topoisomerase I/II selectivity among derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA).

DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride) has high experimental antitumor activity and has completed phase I/II clinical trials. It targets both topoisomerase (topo) I and II, but the roles of each of these enzymes in the antitumour action of DACA are not known. We have used a series of DACA analogues (mainly monosubstituted halogen derivatives) to relate in vitro and in vivo biological activity. We measured topo II selectivity by comparing the inhibition of Jurkat human leukaemia cell lines with high and low topo II content. We determined survival curves following exposure of H460 human lung carcinoma cells for 1 h. We used plasmid DNA to compare the effects of DACA analogues on isolated topo I and II, measuring in particular the inhibition of topo I- and II-mediated DNA relaxation. The results indicate that 5-halogen substituted derivatives are the most active in clonogenic cytotoxicity assays and that this activity is related to their selective activity towards Jurkat cells with high topo II activity. In isolated topo assays, 5-halogen substituted derivatives were also the most potent and in each case the concentration required for inhibition of topo II relaxation was greater than that for inhibition of topo I relaxation. The drug concentration providing efficient cytotoxicity corresponded to that which suppressed the activity of topo I but not of topo II. We hypothesize that DACA analogues act both in vitro and in vivo to simultaneously poison topo II and inhibit topo I catalytic activity, and that this combination contributes to the high antitumour activity of DACA analogues.