INDUCTION OF ENDONUCLEOLYTIC DNA FRAGMENTATION AND APOPTOSIS BY THE DUOCARMYCINS

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