Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma

Atsushi Kitamura, Kazuyuki Matsushita, Yuichi Takiguchi, Hideaki Shimada, Yuji Tada, Makako Yamanaka, Kenzo Hiroshima, Masatoshi Tagawa, Takeshi Tomonaga, Hisahiro Matsubara, Makoto Inoue, Mamoru Hasegawa, Yasunori Sato, David Levens, Koichiro Tatsumi, Fumio Nomura

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17 Citations (Scopus)

Abstract

Human malignant pleural mesothelioma (HMPM) is highly resistant to conventional therapy, and therefore novel therapies are required. We previously reported that overexpression of the FUSE-binding protein-interacting repressor (FIR), a c-myc transcriptional repressor, induces apoptosis via c-Myc suppression, and is thus a suitable cancer therapy. In the current preclinical trial, a fusion gene deleted non-transmissible Sendai virus vector encoding FIR (SeV/ΔF/FIR) was prepared and its cytotoxic activity against an orthotopic xenograft model of HMPM, in combination with cisplatin, was assessed. SeV/ΔF/FIR and a fusion gene deleted non-transmissible Sendai virus vector encoding green fluorescent protein (SeV/ΔF/GFP) were prepared. The transduction efficiency of these agents in terms of dose-dependent cytotoxicity and/or apoptosis induction was then assessed in a few HMPM cells. Combination therapy with SeV/ΔF/FIR plus cisplatin was evaluated in vitro and in a mouse model. SeV/ΔF/FIR significantly reduced cell viability in three HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells. SeV/ΔF/FIR cytotoxicity was partly due to apoptosis induction via c-Myc suppression. In addition, SeV/ΔF/FIR showed synergistic antitumor effects in combination with cisplatin, as was revealed by isobologram analysis in MSTO-211H. Moreover, combination therapy with SeV/ΔF/FIR plus cisplatin demonstrated significant tumor reduction and improvement in survival rate in an animal model. Combination therapy with SeV/ΔF/FIR plus cisplatin has therapeutic potential against HMPM. SeV/ΔF/FIR plus cisplatin will be an attractive modality against HMPM in the future.

Original languageEnglish
Pages (from-to)1366-1373
Number of pages8
JournalCancer science
Volume102
Issue number7
DOIs
Publication statusPublished - 2011 Jul 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kitamura, A., Matsushita, K., Takiguchi, Y., Shimada, H., Tada, Y., Yamanaka, M., Hiroshima, K., Tagawa, M., Tomonaga, T., Matsubara, H., Inoue, M., Hasegawa, M., Sato, Y., Levens, D., Tatsumi, K., & Nomura, F. (2011). Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma. Cancer science, 102(7), 1366-1373. https://doi.org/10.1111/j.1349-7006.2011.01931.x