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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]

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

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