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Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781

Authors' Affiliation: Medical Biophysics Department, British Columbia Cancer Research Center, Vancouver, BC, Canada

Requests for reprints: Peggy L. Olive, Medical Biophysics Department, British Columbia Cancer Research Center, 675 W. 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. Phone: 604-675-8031; Fax: 604-675-8049; E-mail: polive{at}bccrc.ca.

Purpose: PCI-24781 is a novel broad spectrum histone deacetylase inhibitor that is currently in phase I clinical trials. The ability of PCI-24781 to act as a radiation sensitizer and the mechanisms of radiosensitization were examined.

Experimental Design: Exponentially growing human SiHa cervical and WiDr colon carcinoma cells were exposed to 0.1 to 10 µmol/L PCI-24781 in vitro for 2 to 20 h before irradiation and 0 to 4 h after irradiation. Single cells and sorted populations were analyzed for histone acetylation, H2AX phosphorylation, cell cycle distribution, apoptotic fraction, and clonogenic survival.

Results: PCI-24781 treatment for 4 h increased histone H3 acetylation and produced a modest increase in H2AX but negligible cell killing or radiosensitization. Treatment for 24 h resulted in up to 80% cell kill and depletion of cells in S phase. Toxicity reached maximum levels at a drug concentration of 1 µmol/L, and cells in G₁ phase at the end of treatment were preferentially spared. A similar dose-modifying factor (DMF_0.1 = 1.5) was observed for SiHa cells exposed for 24 h at 0.1 to 3 µmol/L, and more radioresistant WiDr cells showed less sensitization (DMF_0.1 = 1.2). Limited radiosensitization and less killing were observed in noncycling human fibroblasts. Cell sorting experiments confirmed that depletion of S-phase cells was not a major mechanism of radiosensitization and that inner noncycling cells of SiHa spheroids could be sensitized by nontoxic doses. PCI-24781 pretreatment increased the fraction of cells with H2AX foci 24 h after irradation but did not affect the initial rate of loss of radiation-induced H2AX or the rate of rejoining of DNA double-strand breaks.

Conclusions: PCI-24781 shows promise as a radiosensitizing agent that may compromise the accuracy of repair of radiation damage.

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