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Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom

Requests for reprints: Mike Walton, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton Surrey, SM2 5NG, United Kingdom. Phone: 44-20-8722-4301; Fax: 44-20-8722-4324. E-mail: Mike.Walton{at}icr.ac.uk

The small-molecule compound pifithrin- (PFT-) has been reported to inhibit p53 function and protect against a variety of genotoxic agents. We show here that PFT- is unstable in tissue culture medium and is rapidly converted to its condensation product PFT-ß. Both compounds showed limited solubility with PFT- precipitating out of tissue culture medium at concentrations >30 µmol/L. PFT- and -ß exhibited cytotoxic effects in vitro towards two human wild-type p53–expressing tumor cell lines, A2780 ovarian and HCT116 colon (IC₅₀ values for both cell lines were 21.3 ± 8.1 µmol/L for PFT- and 90.3 ± 15.5 µmol/L for PFT-ß, mean ± SD, n = 4). There was no evidence of protection by clonogenic assay with either compound in combination with ionizing radiation. Indeed, there was some evidence that PFT- enhanced cytotoxicity, particularly at higher concentrations of PFT-. Neither compound had any effect on p53, p21, or MDM-2 protein expression following ionizing radiation exposure and there was no evidence of any abrogation of p53-dependent, ionizing radiation–induced cell cycle arrest. Similarly, there was no evidence of cellular protection, or of effects on p53-dependent gene transcription, or on translation of MDM-2 or p21 following UV treatment of these human tumor cell lines. In addition, there was no effect on p53 or p21 gene transactivation or p38 phosphorylation after UV irradiation of NIH-3T3 mouse fibroblasts. In conclusion, neither PFT- nor -ß can be regarded as a ubiquitous inhibitor of p53 function, and caution should be exercised in the use of these agents as specific p53 inhibitors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: P. Workman is a Cancer Research UK Life Fellow.

I.R. Hardcastle is currently at the Drug Development Section, Northern Institute of Cancer Research, Chemistry, University of Newcastle upon Tyne, NE1 4RW, United Kingdom.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

² te Poele et al., unpublished data.

Received 12/17/04; revised 6/ 9/05; accepted 7/15/05.