Antitumoral activity of oncolytic vaccinia virus expressing the interferon-induced ds-RNA dependent protein kinase PKR
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[1] Centro Nacional de Biotecnología
Centro Nacional de Biotecnología
Madrid, España
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[2] Fundación para la Investigación Biosanitaria de Andalucía Oriental Alejandro Otero, Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, 18100 Armilla, Granada
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- Localización: Anales de la Real Academia Nacional de Farmacia, ISSN-e 1697-4298, ISSN 0034-0618, Nº. 3, 2010, págs. 327-342
- Idioma: inglés
- Títulos paralelos:
- Actividad oncolítica del virus vaccinia que expresa la proteína quinasa PKR inducida por los interferones y dependiente de RNA bicatenario
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Resumen
Tumour cells generally become more susceptible to virus infection than normal cells due, in part, to a deficient interferon (IFN)-induced antiviral pathway. One of the key IFN-induced enzymes with potent antiviral action is the ds-RNA dependent protein kinase PKR, that once activated blocks protein synthesis, triggers apoptosis and prevents cell growth. Among viruses, vaccinia virus (VACV) lacking selected viral genes or armed with cytokines or tumour specific antigens has been used in preclinical and clinical studies as a therapeutic agent against different tumours. Here we showed in a mouse model of aggressive cancer by subcutaneous inoculation with prostate TRAMP-C1 cells, that a VACV recombinant expressing low levels of human PKR (VV-PKR) and lacking thymidine kinase (TK), is capable of reducing tumour burden when administered by a systemic route in immunocompetent C57/BL6 mice. In addition, expression of PKR was found to attenuate the virus, thus ensuring safety. A catalitically inactive enzyme PKR with a point mutation (K296R) induced similar oncolytic activity as the control virus lacking TK. These findings suggest that VACV recombinants expressing PKR are candidate vectors against cancer cells
