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Departments of ¹ Tumor Biology and ² Oncology, The Norwegian Radium Hospital, Oslo, Norway

Requests for reprints: Anne Hansen Ree, Department of Tumor Biology, The Norwegian Radium Hospital, 0310 Oslo, Norway. Phone: 47-22-934000; Fax: 47-22-522421. E-mail: a.h.ree{at}medisin.uio.no

In breast cancer, radiation has a central role in the treatment of brain metastasis, although tumor sensitivity might be limited. The tumor cell defense response to ionizing radiation involves activation of cell cycle checkpoint signaling. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby aberrations in the chromatin structure, may also override the DNA damage defense response and facilitate the radiation-induced mitotic cell death. In experimental metastasis models, the human breast carcinoma cell line MA-11 invariably disseminates to the central nervous system. We compared profiles of in vitro MA-11 cell cycle response to ionizing radiation and HDAC inhibition. After radiation exposure, the G₂-M phase accumulation and the preceding repression of the G₂ phase regulatory factors Polo-like kinase-1 and cyclin B1 required intact G₂ checkpoint signaling through the checkpoint kinase CHK1, whereas the similar phenotypic changes observed with HDAC inhibition did not. MA-11 cells did not show radiation-induced expression of the G₁ cell cycle inhibitor p21, indicative of a defective G₁ checkpoint and consistent with a point mutation detected in the tumor suppressor TP53 gene. Increase in the p21 level, however, was observed with HDAC inhibition. Following pretreatment with the HDAC inhibitor, the efficiency of clonogenic regrowth after irradiation was reduced, which is in accordance with the concept of increased probability of mitotic cell death when the chromatin structure is disrupted. Among molecular cell cycle–targeted drugs currently in the pipeline for testing in early-phase clinical trials, HDAC inhibitors may have therapeutic potential as radiosensitizers.

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³ http://p53.genome.ad.jp

Received 11/12/04; revised 5/16/05; accepted 6/14/05.