Abstract
Vorinostat (suberoylanilide hydroxamic acid), a histone deacetylase inhibitor, is currently undergoing clinical evaluation as therapy for cancer. We investigated the effects of vorinostat on tumor cell radiosensitivity in a breast cancer brain metastasis model using MDA-MB-231-BR cells. In vitro radiosensitivity was evaluated using clonogenic assay. Cell cycle distribution and apoptosis was measured using flow cytometry. DNA damage and repair was evaluated using γH2AX. Mitotic catastrophe was measured by immunostaining. Growth delay and intracranial xenograft models were used to evaluate the in vivo tumor radiosensitivity. Cells exposed to vorinostat for 16 hours before and maintained in the medium after irradiation had an increase in radiosensitivity with a dose enhancement factor of 1.57. γH2AX, as an indicator of double-strand breaks, had significantly more foci per cell in the vorinostat plus irradiation group. Mitotic catastrophe, measured at 72 hours, was significantly increased in cells receiving vorinostat plus irradiation. Irradiation of s.c. MDA-MB-231-BR tumors in mice treated with vorinostat resulted in an increase in radiation-induced tumor growth delay. Most importantly, animals with intracranial tumor implants lived the longest after combination treatment. These results indicate that vorinostat enhances tumor cell radiosensitivity in vitro and in vivo. There was a greater than additive improvement in survival in our intracranial model. Combining vorinostat with radiation may be a potential treatment option for patients with breast cancer who develop brain metastases. [Mol Cancer Ther 2009;8(6):1589–95]
- vorinostat
- SAHA
- HDAC
- radiosensitization
Footnotes
Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Department of Defense Breast Cancer Research Program grant W81 XWH-062-0033 (P.S. Steeg and K. Camphausen). A. Baschnagel was supported through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer, Inc. (via a grant to the Foundation for NIH from Pfizer, Inc.).
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 January 15, 2009.
- Revision received March 2, 2009.
- Accepted March 3, 2009.
- © 2009 American Association for Cancer Research.