Urokinase-targeted fusion by oncolytic sendai virus eradicates orthotopic glioblastomas by pronounced synergy with interferon-β gene

Yuzo Hasegawa, Hiroaki Kinoh, Yasuo Iwadate, Mitsuho Onimaru, Yasuji Ueda, Yui Harada, Satoru Saito, Aki Furuya, Takashi Saegusa, Yosuke Morodomi, Mamoru Hasegawa, Shigeyoshi Saito, Ichio Aoki, Naokatsu Saeki, Yoshikazu Yonemitsu

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Abstract

Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity rSeV/dMFct14 (uPA2), named BioKnife for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-Β (IFN-Β) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-Β (BioKnife-IFNΒ) , cell-cell fusion of 9L-L/R strongly facilitated the expression of IFN-Β, and in turn, IFN-Β significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNΒ may have significant potential to improve the survival of GM patients in a clinical setting.

Original languageEnglish
Pages (from-to)1778-1786
Number of pages9
JournalMolecular Therapy
Volume18
Issue number10
DOIs
Publication statusPublished - Oct 2010

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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