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A combination of IFN-β and temozolomide in human glioma xenograft models: implication of p53-mediated MGMT downregulation

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Abstract

Purpose

Methylation of the O6-methyguanine-DNA methyltransferase (MGMT) gene promoter in gliomas has been reported to be a useful predictor of the responsiveness to temozolomide (TMZ). In our previous experiments, we observed that IFN-β sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this study, (1) we explored the synergistic effect of IFN-β and TMZ in the animal model, and (2) clarified the role of IFN-β induced TP53 in the human MGMT promoter.

Methods

(1) Nude mice with either subcutaneous T98 (TMZ-resistant) or U251SP (TMZ-sensitive) tumor were treated with IFN-β/TMZ for 5 consecutive days. (2) The MGMT promoter activity was assayed by a luciferase reporter system in Saos2 (p53-null) cells transduced with a p53-adenoviral vector, and T98 glioma cells treated with IFN-β.

Results

(1) A combination of IFN-β/TMZ had significant synergistic antitumor activity on the growth of both T98 and U251SP tumors. (2) MGMT promoter activity was suppressed by either adenovirally transduced p53 or IFN-β.

Conclusions

It would be appealing to consider a prospective clinical trial in which genetic markers are used for personalized drug selection, eliciting other forms of treatment or inhibition of MGMT for those with MGMT expression. In this context, IFN-β inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ.

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Authors and Affiliations

  1. Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan

    Atsushi Natsume, Toshihiko Wakabayashi, Dai Ishii, Hideharu Maruta, Masazumi Fujii, Shinji Shimato, Motokazu Ito & Jun Yoshida

  2. The Center for Genetic and Regenerative Medicine, Nagoya University Hospital, Nagoya, Japan

    Atsushi Natsume, Toshihiko Wakabayashi & Jun Yoshida

Authors
  1. Atsushi Natsume
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  2. Toshihiko Wakabayashi
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  3. Dai Ishii
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  4. Hideharu Maruta
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  5. Masazumi Fujii
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  6. Shinji Shimato
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  7. Motokazu Ito
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  8. Jun Yoshida
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Correspondence to Jun Yoshida.

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Natsume, A., Wakabayashi, T., Ishii, D. et al. A combination of IFN-β and temozolomide in human glioma xenograft models: implication of p53-mediated MGMT downregulation. Cancer Chemother Pharmacol 61, 653–659 (2008). https://doi.org/10.1007/s00280-007-0520-x

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  • DOI: https://doi.org/10.1007/s00280-007-0520-x

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