This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Natsume, A. Articles by Yoshida, J. Search for Related Content PubMed PubMed Citation Articles by Natsume, A. Articles by Yoshida, J.

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.

This article has been cited by other articles:

				S. OSHIRO, H. TSUGU, F. KOMATSU, T. OHMURA, M. OHTA, S. SAKAMOTO, T. FUKUSHIMA, and T. INOUE Efficacy of Temozolomide Treatment in Patients with High-grade Glioma Anticancer Res, March 1, 2009; 29(3): 911 - 917. [Abstract] [Full Text] [PDF]

				K. Miyashita, K. Kawakami, M. Nakada, W. Mai, A. Shakoori, H. Fujisawa, Y. Hayashi, J.-i. Hamada, and T. Minamoto Potential Therapeutic Effect of Glycogen Synthase Kinase 3{beta} Inhibition against Human Glioblastoma Clin. Cancer Res., February 1, 2009; 15(3): 887 - 897. [Abstract] [Full Text] [PDF]

				S. F. Rosati, R. F. Williams, L. C. Nunnally, M. C. McGee, T. L. Sims, L. Tracey, J. Zhou, M. Fan, C. Y. Ng, A. C. Nathwani, et al. IFN-{beta} sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression Mol. Cancer Ther., December 1, 2008; 7(12): 3852 - 3858. [Abstract] [Full Text] [PDF]

				M. Zheng, D. Bocangel, R. Ramesh, S. Ekmekcioglu, N. Poindexter, E. A. Grimm, and S. Chada Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methyltransferase in human melanoma cells Mol. Cancer Ther., December 1, 2008; 7(12): 3842 - 3851. [Abstract] [Full Text] [PDF]

				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]