Cell killing by the novel imidazoacridinone antineoplastic agent, C-1311, is inhibited at high concentrations coincident with dose-differentiated cell cycle perturbation

We have studied the actions of C-1311, an imidazoacridinone analogue with potent in vivo antitumour activity, against a human tumour line (HeLa S3), in an examination of the events associated with the lethality of this agent. Continuous exposures (24 h) induced complete G(2) arrest, although the concentration range of this effect was narrow, with elevation of the drug level inducing additional and increasing impediment to S-phase transit. Acute treatments (3 h) revealed that cells exposed to drug levels, which first induced persistent G(2) arrest (0.5 mu g ml(-1)), subsequently died from this compartment, while doses exceeding these levels (1.0 mu g ml(-1)), paradoxically, did not cause the same extensive cell death. We explain our findings on the proposition that this particular mode of cell death is dependent upon inappropriate activation of the primed mitotic machinery-specifically the hyperphosphorylated p34(cdc2)/cyclin B complex-assembled within G(2), but that impediment to genomic replication at higher doses inhibits assembly of this complex, and hence prevents cell death. Our results demonstrate that high dose does not necessarily correlate with increased cell death, while at the same time providing further evidence for the importance of events normally associated with the G(2)/M transition in DNA damage-induced tumour cell death.