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UCN-01 Enhances the In Vitro Toxicity of Clinical Agents in Human Tumor Cell Lines

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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.

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Authors and Affiliations

  1. SAIC-Frederick, NCI-FCRDC, Frederick, MD, USA

    Anne Monks, Erik D. Harris, Anne Vaigro-Wolff, Curtis D. Hose & John W. Connelly

  2. Developmental Therapeutics Program, DCTD, NCI, Rockville, MD, USA

    Edward A. Sausville

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  1. Anne Monks
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  2. Erik D. Harris
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  3. Anne Vaigro-Wolff
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  4. Curtis D. Hose
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  5. John W. Connelly
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  6. Edward A. Sausville
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Monks, A., Harris, E.D., Vaigro-Wolff, A. et al. UCN-01 Enhances the In Vitro Toxicity of Clinical Agents in Human Tumor Cell Lines. Invest New Drugs 18, 95–107 (2000). https://doi.org/10.1023/A:1006313611677

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