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Research Articles: Therapeutics

Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275

Departments of ¹ Neurosurgery and ² Neuropathology, University of Erlangen-Nuremberg, Erlangen-Nuremberg, Germany; ³ Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; ⁴ Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany; ⁵ Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands; and ⁶ Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

Requests for reprints: Ilker Y. Eyüpoglu, Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. Phone: 49-9131-85-34418; Fax: 49-9131-85-26033. E-mail: eyupoglu{at}gmx.net

Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC₉₀, 3.75 µmol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G₀-G₁ cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein–transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 µmol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas. [Mol Cancer Ther 2006;5(5):1248–55]

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.

Note: I.Y. Eyüpoglu and E. Hahnen contributed equally as first authors.

Received 12/20/05; revised 2/ 7/06; accepted 3/ 2/06.

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