INDUCTION OF ENDONUCLEOLYTIC DNA FRAGMENTATION AND APOPTOSIS BY THE DUOCARMYCINS

The duocarmycins are exceptionally potent, naturally occurring antitumor antibiotics related to (+)-CC-1065. Short term exposure (1-4 h) of Molt-4 or L-1210 cells to the agents produced internucleosomal DNA fragmentation in approximately 200 base-pair multiples and at dose levels as low as 100 pM produced morphological changes characteristic of programmed cell death. These results were associated with strong inhibition of suspension culture growth and clonogenic survival suggesting that at physiologically relevant concentrations the agents induced cell death by a target cell activated pathway. Presumably, this is the consequence of the sequence selective alkylation of DNA by the duocarmycins potentially at internucleosomal sites, followed by intracellular signalling with activation of endonucleases, to trigger the apoptotic cell death mechanism.