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

Invest New Drugs. 2000 May;18(2):95-107. doi: 10.1023/a:1006313611677.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids / toxicity*
  • Antineoplastic Agents / toxicity*
  • Antineoplastic Agents, Alkylating / toxicity
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Death / drug effects
  • Drug Synergism
  • Humans
  • Mitotic Index
  • Protein Kinase C / antagonists & inhibitors
  • Staurosporine / analogs & derivatives
  • Thiotepa / toxicity
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics


  • Alkaloids
  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Tumor Suppressor Protein p53
  • 7-hydroxystaurosporine
  • Thiotepa
  • Protein Kinase C
  • Staurosporine