UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines

UCN-01 is undergoing Phase I evaluation and is a candidate for combination strategies in the clinic. UCN-01 has been shown to have a variety of effect s on cellular targets and the cell cycle. It has also been reported to sens itize cells to several clinical drugs in vitro, possibly in a manner relate d to p53 status. Thus, combinations of UCN-01 with a series of clinical age nts in variety of cell lines have been investigated in vitro. Certain cell lines demonstrated synergistic interactions with combinations of UCN-01 (20 -150 nM) and thiotepa, mitomycin C, cisplatin, melphalan, topotecan, gemcit abine, fludarabine or 5-fluorouracil. In contrast, UCN-01 combinations with the antimitotic agents, paclitaxel and vincristine, or topoisomerase II in hibitors, adriamycin and etoposide, did not result in synergy, only in addi tive toxicity. Cells with non-functional p53 were significantly more suscep tible to the supra-additive effects of certain DNA-damaging agents and UCN- 01 combinations, than cells expressing functional p53 activity. In contrast , there was no significant relationship between p53 status and susceptibili ty to synergy between antimetabolites and UCN-01. The mechanism behind the observed synergy appeared unrelated to effects on protein kinase C or abrog ation of the cell cycle in G2. Moreover, increased apoptosis did not fully explain the supradditive response. These data indicate that UCN-01 sensitiz es a variety of cell lines to certain DNA-damaging agents (frequently coval ent DNA-binding drugs) and antimetabolites in vitro, but the mechanism unde rlying this interaction remains undefined.