Engineering of double recombinant vaccinia virus with enhanced oncolytic potential for solid tumor virotherapy.

Abstract

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.

• Authors: Galina Kochneva, Galina Sivolobova, Anastasiya Tkacheva, Antonina Grazhdantseva, Olga Troitskaya, Anna Nushtaeva, Anastasiya Tkachenko, Elena Kuligina, Vladimir Richter, Olga Koval
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 45 Pg. 74171-74188 (Nov 08 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27708236 (Publication Type: Journal Article)

Chemical References

• Caseins
• lactaptin, human
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• A549 Cells
• Animals
• Apoptosis
• Caseins (biosynthesis, genetics)
• Cell Line, Tumor
• Chlorocebus aethiops
• Female
• Genetic Engineering (methods)
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis, genetics)
• Humans
• MCF-7 Cells
• Mice
• Mice, SCID
• Neoplasms (therapy, virology)
• Oncolytic Virotherapy (methods)
• Vaccinia virus (genetics, metabolism, physiology)