2011 Fiscal Year Final Research Report
Development of'BioKnife', a uPA-targeted oncolytic Sendai virus to treat intractable malignancies.
| Project/Area Number |
22659246
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Digestive surgery
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
YONEMITSU Yoshikazu 九州大学, 薬学研究院, 教授 (40315065)
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| Project Period (FY) |
2010 – 2011
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| Keywords | 悪性胸膜中皮腫 / バイオナイフ / センダイウイルス / NF-κB / RIG-Iヘリカーゼ |
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| Research Abstract |
Malignant pleural mesothelioma(MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor(uPAR). We here examined the potential of our new and powerful recombinant Sendai virus(rSeV), which shows uPAR-specific cell-to-cell fusion activity(rSeV/dMFct14(uPA2), named“BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis. Such an effect was also seen on both MSTO-211H and H226 cells in vitro ; however, we confirmed that the latter expressed uPAR but not uPA. Of interest, infection with BioKnife strongly facilitated the uPA release from H226 cells, and this effect was completely abolished by use of either pyrrolidine dithiocarbamate or BioKnife expressing the C-terminus-deleted dominant negative inhibitor for retinoic acid-inducible gene-I(RIG-IC), indicating that BioKnife-dependent expression of uPA was mediated by the RIG-I/NK-κB axis, detecting RNA viral genome replication. Therefore, these results suggest a proof of concept that the tumor cell-killing mechanism via BioKnife may have significant potential to treat patients with MPM that is characterized by frequent uPAR expression in a clinical setting.
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Research Products
(69 results)
