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IFN-ß Down-Regulates the Expression of DNA Repair Gene MGMT and Sensitizes Resistant Glioma Cells to Temozolomide

¹ Center for Genetic and Regenerative Medicine, Nagoya University Hospital; ² Department of Neurosurgery, Nagoya University School of Medicine; and ³ Department of Molecular Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

Requests for reprints: Atsushi Natsume, Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, 4668550 Nagoya, Aichi, Japan. Phone: 81-52-744-2353; Fax: 81-52-744-2360; E-mail: anatsume{at}med.nagoya-u.ac.jp.

Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-ß can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-ß sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-ß was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-ß using appropriate doses and schedules of administration.

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				T. Wakabayashi, T. Kayama, R. Nishikawa, H. Takahashi, T. Yoshimine, N. Hashimoto, T. Aoki, K. Kurisu, A. Natsume, M. Ogura, et al. A Multicenter Phase I Trial of Interferon-{beta} and Temozolomide Combination Therapy for High-grade Gliomas (INTEGRA Study) Jpn. J. Clin. Oncol., October 1, 2008; 38(10): 715 - 718. [Abstract] [Full Text] [PDF]