title: UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines.
abstract: 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 effects on cellular targets and the cell cycle. It has also been reported to sensitize cells to several clinical drugs in vitro, possibly in a manner related to p53 status. Thus, combinations of UCN-01 with a series of clinical agents 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, gemcitabine, fludarabine or 5-fluorouracil. In contrast, UCN-01 combinations with the antimitotic agents, paclitaxel and vincristine, or topoisomerase II inhibitors, adriamycin and etoposide, did not result in synergy, only in additive toxicity. Cells with non-functional p53 were significantly more susceptible 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 susceptibility to synergy between antimetabolites and UCN-01. The mechanism behind the observed synergy appeared unrelated to effects on protein kinase C or abrogation of the cell cycle in G2. Moreover, increased apoptosis did not fully explain the supradditive response. These data indicate that UCN-01 sensitizes a variety of cell lines to certain DNA-damaging agents (frequently covalent DNA-binding drugs) and antimetabolites in vitro, but the mechanism underlying this interaction remains undefined.
authors.affiliation: SAIC-Frederick, NCI-FCRDC, MD 21702, USA.
authors.forename: A
authors.initials: A
authors.lastname: Monks
authors.forename: E D
authors.initials: ED
authors.lastname: Harris
authors.forename: A
authors.initials: A
authors.lastname: Vaigro-Wolff
authors.forename: C D
authors.initials: CD
authors.lastname: Hose
authors.forename: J W
authors.initials: JW
authors.lastname: Connelly
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000470:Alkaloids / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008940:Mitotic Index; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000031:analogs & derivatives; D013852:Thiotepa / Q000633:toxicity; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D013852:Thiotepa; D011493:Protein Kinase C; D019311:Staurosporine