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¹ Department of Radiation Oncology, Neurological Surgery, and Comprehensive Cancer Center and ² Department of Pathology and Neurological Surgery, University of California at San Francisco, San Francisco, California; ³ Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva, Israel; and ⁴ Chemistry Department, Bar Ilan University, Ramat Gan, Israel

Requests for reprints: Michal Entin-Meer, Comprehensive Cancer Center, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94115. Phone: 415-476-0543; Fax: 415-502-3179. E-mail: memeer{at}cc.ucsf.edu

Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate (AN-1), induced hyperacetylation, increased p21^Cip1 expression, inhibited proliferation, and enhanced apoptosis. Histone deacetylase inhibitor–induced apoptosis was mediated primarily by caspase-8. Treatment of cells with AN-1 or AN-9 for 24 hours before exposure to -irradiation potentiated further caspase-8 activity and resultant apoptosis. Clonogenic survival curves revealed marked reductions in cell renewal capacity of U251 MG cells exposed to combinations of AN-1 and radiation. Preliminary in vivo experiments using human glioma cell lines grown as xenografts in mouse flanks suggest in vivo efficacy of AN-9. The data suggest that novel butyric acid prodrugs provide a promising treatment strategy for malignant gliomas as single agents and in combination with radiation therapy. [Mol Cancer Ther 2005;4(12):1952-61]

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.

⁵ G. Afshar, et al. Radiation-induced caspase-8 expression mediates p53-independent apoptosis in glioma cells, submitted for publication.

Received 3/25/05; revised 8/19/05; accepted 9/21/05.

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