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 G2 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 G2 arrest (0.5 microgram ml-1), subsequently died from this compartment, while doses exceeding these levels (1.0 microgram 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 p34cdc2/cyclin B complex-assembled within G2, 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 G2/M transition in DNA damage-induced tumour cell death.
Lamb
J
J
Cell Pathology Unit, University Medical School, Foresterhill, Aberdeen, UK.
Wheatley
D N
DN
D000609:Aminoacridines / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000032:analysis / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D013997:Time Factors; D014410:Tumor Stem Cell Assay
D000609:Aminoacridines; D000970:Antineoplastic Agents; D004247:DNA; C098965:C 1311