title: 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.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.|State Research Center of Virology and Biotechnology "Vector", Koltsovo, Russia.
authors.forename: Galina
authors.initials: G
authors.lastname: Kochneva
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.|State Research Center of Virology and Biotechnology "Vector", Koltsovo, Russia.
authors.forename: Galina
authors.initials: G
authors.lastname: Sivolobova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.|State Research Center of Virology and Biotechnology "Vector", Koltsovo, Russia.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Tkacheva
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.|State Research Center of Virology and Biotechnology "Vector", Koltsovo, Russia.
authors.forename: Antonina
authors.initials: A
authors.lastname: Grazhdantseva
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Troitskaya
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Nushtaeva
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Tkachenko
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Kuligina
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Richter
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.|Novosibirsk State University, Novosibirsk, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Koval
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D002364:Caseins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D002364:Caseins; C551270:lactaptin, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: GM-CSF; apoptosis; chemoresistant tumor; lactaptin; vaccinia virus