gms | German Medical Science

57th Annual Meeting of the German Society of Neurosurgery
Joint Meeting with the Japanese Neurosurgical Society

German Society of Neurosurgery (DGNC)

11 - 14 May, Essen

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Preclinical studies to evaluate the antitumor effect of Interferon-beta and Temozolomide combination against malignant glioma

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  • corresponding author J. Yoshida - Department of Neurosurgery, Nagoya University Graduate School of Medicine
  • A. Natsume - Department of Neurosurgery, Nagoya University Graduate School of Medicine
  • T. Wakabayashi - Department of Neurosurgery, Nagoya University Graduate School of Medicine
  • M. Mizuno - Department of Neurosurgery, Nagoya University Graduate School of Medicine

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 57. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie. Essen, 11.-14.05.2006. Düsseldorf, Köln: German Medical Science; 2006. DocSO.03.02

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dgnc2006/06dgnc174.shtml

Published: May 8, 2006

© 2006 Yoshida et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Objective: Temozolomide (TMZ) is a well-tolerated, orally bioactive alkylating agent, which forms cross-links between adjacent strands of DNA, leading to cell death. The DNA repair protein, O6-methyguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistant to alkylating agents, and it was reported that methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness to TMZ. On the other hand, Type I interferon (IFN), as a drug sensitizer, has been widely used in combination with other antitumor agents such as nitrosoureas. In our previous experiments (Cancer Res 2005;65:7573-9), we found that IFN-β sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter. For the mechanism of action, oligonucleotide microarray, RNAi experiments and ChIP assay revealed that sensitizing effect of IFN-β was possibly due to attenuation of MGMT expression via induction of TP53. Based on these results, the aim of this study is further to explore the synergistic effect of IFN-β and TMZ on nude mice with subcutaneously (s.c.) transplanted human glioma.

Methods: Mice were randomized to separate into six groups (five to six animals per group) and treated when s.c. tumors had reached a volume of between 200 and 400 mm3. IFN-β (2x105 IU per animal) was given i.p. 6 h before i.p. injection of TMZ (50 or 100 mg/kg). Control mice, or mice receiving IFN-β or TMZ alone, also received the corresponding vehicle. Treatments were repeated at 24-hr intervals for a total of five doses.

Results: IFN-β alone did not decrease the tumor growth significantly. TMZ (100 mg/kg) alone suppressed the tumor growth, but did increase the associated body weight loss. In contrast, a combination of IFN-β and 50-mg/kg dose of TMZ decreased the tumor growth very significantly, and complete regression was observed in one of five animals (20%).

Conclusions: The results suggest that prior administration of IFN-β can lead to an increase in the therapeutic index of TMZ.