ISSN:
1573-0646
Keywords:
UCN-01
;
combination
;
synergy
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Abstract UCN-01 is undergoing Phase I evaluation and is a candidate forcombination strategies in the clinic. UCN-01 has been shown to havea variety of effects on cellular targets and the cell cycle. It hasalso been reported to sensitize cells to several clinical drugsin vitro, possibly in a manner related to p53 status. Thus,combinations of UCN-01 with a series of clinical agents in varietyof cell lines have been investigated in vitro. Certain celllines demonstrated synergistic interactions with combinations ofUCN-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 andvincristine, or topoisomerase II inhibitors, adriamycin andetoposide, did not result in synergy, only in additive toxicity.Cells with non-functional p53 were significantly more susceptibleto the supra-additive effects of certain DNA-damaging agents andUCN-01 combinations, than cells expressing functional p53 activity.In contrast, there was no significant relationship between p53status and susceptibility to synergy between antimetabolites andUCN-01. The mechanism behind the observed synergy appearedunrelated to effects on protein kinase C or abrogation of the cellcycle in G2. Moreover, increased apoptosis did not fully explainthe supradditive response. These data indicate that UCN-01sensitizes a variety of cell lines to certain DNA-damaging agents(frequently covalent DNA-binding drugs) and antimetabolites invitro, but the mechanism underlying this interaction remainsundefined.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1006313611677
Permalink
