Cytotoxic effects of cell cycle phase specific agents: result of cell cycle perturbation

Although agents which act in a cell cycle phase specific manner are commonly used in the clinic and in basic research, it is as yet unclear why these agents are cytotoxic. In this paper, we examine the cellular events associated with the cytotoxicity of aphidicolin and vincristine in CHO strain AA8 cells. Cell killing resulting from aphidicolin treatment was found to require a period of inhibition-free growth following removal of the drug and was associated with characteristic aberrant mitotic processes. The cytotoxic effects of aphidicolin could be antagonized by the concomitant inhibition of protein synthesis with cycloheximide in the period of DNA synthesis inhibition. Cell killing resulting from treatment with vincristine was associated with the aberrant segregation of nuclear material and the formation of multiple partial nuclei. Vincristine cytotoxicity was found to be antagonized by concomitant administration of cycloheximide or cytochalasin D. These data support a hypothesis that the cytotoxic effects of cell cycle phase specific agents do not derive directly from their biochemical actions per se. We propose that cell death results from processes that are evoked by dissociation of normally integrated cell cycle events, and that dissociation involves replicative/mitotic events in the case of aphidicolin and karyokinetic/nuclear reformation events in the case of vincristine.