Engineering of double recombinant vaccinia virus with enhanced oncolytic potential for solid tumor virotherapy
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Galina Kochneva1,2, Galina Sivolobova1,2, Anastasiya Tkacheva1,2, Antonina Grazhdantseva1,2, Olga Troitskaya1,3, Anna Nushtaeva1, Anastasiya Tkachenko1, Elena Kuligina1, Vladimir Richter1, Olga Koval1,3
1Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
2State Research Center of Virology and Biotechnology “Vector”, Koltsovo, Russia
3Novosibirsk State University, Novosibirsk, Russia
Olga Koval, email: [email protected]
Keywords: vaccinia virus, chemoresistant tumor, apoptosis, lactaptin, GM-CSF
Received: June 03, 2016 Accepted: September 21, 2016 Published: September 30, 2016
Vaccinia virus (VACV) oncolytic therapy has been successful in a number of tumor models. In this study our goal was to generate a double recombinant vaccinia virus (VV-GMCSF-Lact) with enhanced antitumor activity that expresses exogenous proteins: the antitumor protein lactaptin and human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lactaptin has previously been demonstrated to act as a tumor suppressor in mouse hepatoma as well as MDA-MB-231 human adenocarcinoma cells grafted into SCID mice. VV-GMCSF-Lact was engineered from Lister strain (L-IVP) vaccinia virus and has deletions of the viral thymidine kinase and vaccinia growth factor genes. Cell culture experiments revealed that engineered VV-GMCSF-Lact induced the death of cultured cancer cells more efficiently than recombinant VACV coding only GM-CSF (VV-GMCSF-dGF). Normal human MCF-10A cells were resistant to both recombinants up to 10 PFU/cell. The selectivity index for breast cancer cells measured in pair cultures MCF-7/MCF-10A was 200 for recombinant VV-GMCSF-Lact coding lactaptin and 100 for VV-GMCSF-dGF. Using flow cytometry we demonstrated that both recombinants induced apoptosis in treated cells but that the rate in the cells with active caspase-3 and -7 was higher after treatment with VV-GMCSF-Lact than with VV-GMCSF-dGF. Tumor growth inhibition and survival outcomes after VV-GMCSF-Lact treatment were estimated using immunodeficient and immunocompetent mice models. We observed that VV-GMCSF-Lact efficiently delays the growth of sensitive and chemoresistant tumors. These results demonstrate that recombinant VACVs coding an apoptosis-inducing protein have good therapeutic potential against chemoresistant tumors. Our data will also stimulate further investigation of coding lactaptin double recombinant VACV in clinical settings.
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