This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Camphausen, K. Articles by Tofilon, P. J. Search for Related Content PubMed PubMed Citation Articles by Camphausen, K. Articles by Tofilon, P. J.

¹ Radiation Oncology Branch and ² Molecular Radiation Therapeutics Branch, National Cancer Institute, Bethesda, MD

Requests for Reprints: Philip J. Tofilon, Molecular Radiation Therapeutics Branch, Radiation Oncology Sciences Program, EPN/6015A, 6130 Executive Boulevard, MSC 7440, Rockville, MD 20852-7440. Phone: (301) 496-6336. E-mail: tofilonp{at}mail.nih.gov

Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor, which has recently entered clinical trials. However, when administered as a single agent against solid tumors, the antitumor actions of flavopiridol have been primarily cytostatic. Given its reported effects on cell cycle regulation, transcription, and apoptosis, flavopiridol may also influence cellular radioresponse. Thus, to evaluate the potential for combining this cyclin-dependent kinase inhibitor with radiation as a cancer treatment strategy, we have investigated the effects of flavopiridol on the radiation sensitivity of two human prostate cancer cell lines (DU145 and PC3). The data presented here indicate that exposure to flavopiridol (60–90 nM) after irradiation enhanced the radiosensitivity of both DU145 and PC3 cells. This sensitization occurred in the absence of significant reductions in cell proliferation, retinoblastoma protein phosphorylation, or P-TEFb activity. Moreover, the post-irradiation addition of flavopiridol had no effect on radiation-induced apoptosis or the activation of the G₂ cell cycle checkpoint. However, flavopiridol did modify the time course of H2AX expression in irradiated cells. Whereas there was no significant difference in radiation-induced H2AX foci at 6 h, at 24 h after irradiation, the number of cells expressing H2AX foci was significantly greater in the flavopiridol-treated cells. These results indicate that flavopiridol can enhance radiosensitivity of human tumor cells and suggest that this effect may involve an inhibition of DNA repair.

Key Words: Flavopiridol • radiosensitization • human tumor cells • H2AX

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.

Received 11/10/03; revised 1/22/04; accepted 2/ 6/04.