Urokinase-targeted fusion by oncolytic Sendai virus eradicates orthotopic glioblastomas by pronounced synergy with interferon-β gene.
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.
Hasegawa
Yuzo
Y
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Kinoh
Hiroaki
H
Iwadate
Yasuo
Y
Onimaru
Mitsuho
M
Ueda
Yasuji
Y
Harada
Yui
Y
Saito
Satoru
S
Furuya
Aki
A
Saegusa
Takashi
T
Morodomi
Yosuke
Y
Hasegawa
Mamoru
M
Saito
Shigeyoshi
S
Aoki
Ichio
I
Saeki
Naokatsu
N
Yonemitsu
Yoshikazu
Y
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000235:genetics / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D055293:Receptors, Urokinase Plasminogen Activator; D016899:Interferon-beta; D014568:Urokinase-Type Plasminogen Activator