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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Bull, E. E. A. Articles by Tofilon, P. J. Search for Related Content PubMed PubMed Citation Articles by Bull, E. E. A. Articles by Tofilon, P. J.

Enhanced Tumor Cell Radiosensitivity and Abrogation of G₂ and S Phase Arrest by the Hsp90 Inhibitor 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin

¹ Molecular Radiation Therapeutics Branch, ² Radiation Oncology Branch, ³ Developmental Therapeutics Program, National Cancer Institute, Bethesda, Maryland, and ⁴ Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland

Purpose: Because of the potential for affecting multiple signaling pathways, inhibition of Hsp90 may provide a strategy for enhancing tumor cell radiosensitivity. Therefore, we have investigated the effects of the orally bioavailable Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on the radiosensitivity of human tumor cells in vitro and grown as tumor xenografts.

Experimental Design: The effect of 17-DMAG on the levels of three proteins (Raf-1, ErbB2, and Akt) previously implicated in the regulation of radiosensitivity was determined in three human solid tumor cell lines. A clonogenic assay was then used to evaluate cell survival after exposure to 17-DMAG followed by irradiation. For mechanistic insight, the G₂- and S-phase checkpoints were evaluated in 17-DMAG–treated cells. Finally, the effect of in vivo administration of 17-DMAG in combination with radiation on the growth rate of xenograft tumors was determined.

Results: 17-DMAG exposure reduced the levels of the three radiosensitivity-associated proteins in a cell line-specific manner with ErbB2 being the most susceptible. Corresponding concentrations of 17-DMAG enhanced the radiosensitivity of each of the tumor cell lines. This sensitization seemed to be the result of a 17-DMAG–mediated abrogation of the G₂- and S-phase cell cycle checkpoints. The oral administration of 17-DMAG to mice bearing tumor xenografts followed by irradiation resulted in a greater than additive increase in tumor growth delay.

Conclusions: These data indicate that 17-DMAG enhances the in vitro and in vivo radiosensitivity of human tumor cells. The mechanism responsible seems to involve the abrogation of radiation-induced G₂- and S-phase arrest.

This article has been cited by other articles:

				T. T. Koll, S. S. Feis, M. H. Wright, M. M. Teniola, M. M. Richardson, A. I. Robles, J. Bradsher, J. Capala, and L. Varticovski HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair Mol. Cancer Ther., July 1, 2008; 7(7): 1985 - 1992. [Abstract] [Full Text] [PDF]

				K. Camphausen and P. J. Tofilon Inhibition of Hsp90: A Multitarget Approach to Radiosensitization Clin. Cancer Res., August 1, 2007; 13(15): 4326 - 4330. [Abstract] [Full Text] [PDF]

				A. I. Robles, M. H. Wright, B. Gandhi, S. S. Feis, C. L. Hanigan, A. Wiestner, and L. Varticovski Schedule-Dependent Synergy between the Heat Shock Protein 90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin and Doxorubicin Restores Apoptosis to p53-Mutant Lymphoma Cell Lines. Clin. Cancer Res., November 1, 2006; 12(21): 6547 - 6556. [Abstract] [Full Text] [PDF]

				H. Dote, W. E. Burgan, K. Camphausen, and P. J. Tofilon Inhibition of hsp90 compromises the DNA damage response to radiation. Cancer Res., September 15, 2006; 66(18): 9211 - 9220. [Abstract] [Full Text] [PDF]

				H. Dote, D. Cerna, W. E. Burgan, K. Camphausen, and P. J. Tofilon ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition Cancer Res., August 1, 2005; 65(15): 6967 - 6975. [Abstract] [Full Text] [PDF]