title: Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro.
abstract: Tumour resistance to a wide range of drugs (multiple drug resistant, MDR) acquired after intensive chemotherapy is considered to be the main obstacle of the curative treatment of cancer patients. Recent work has shown that oncolytic viruses demonstrated prominent potential for effective treatment of diverse cancers. Here, we evaluated whether genetically modified vaccinia virus (LIVP-GFP) may be effective in treatment of cancers displaying MDR phenotype.
  
  
  
  LIVP-GFP replication, transgene expression and cytopathic effects were analysed in human cervical carcinomas KB-3-1 (MDR-), KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), murine lymphosarcomas RLS and RLS-40 (MDR+). To investigate the efficacy of this therapy in vivo, we treated immunocompetent mice bearing murine lymphosarcoma RLS-40 (MDR+) (6- to 8-week-old female CBA mice; n = 10/group) or melanoma B-16 (MDR-) (6- to 8-week-old female C57Bl mice; n = 6/group) with LIVP-GFP (5 × 10(7) PFU of virus in 0.1 mL of IMDM immediately and 4 days after tumour implantation).
  
  
  
  We demonstrated that LIVP-GFP replication was effective in human cervical carcinomas KB-3-1 (MDR-) and KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), whereas active viral production was not detected in murine lymphosarcomas RLS and RLS-40 (MDR+). Additionally, it was found that in tumour models in immunocompetent mice under the optimized regimen intratumoural injections of LIVP-GFP significantly inhibited melanoma B16 (33 % of mice were with complete response after 90 days) and RLS-40 tumour growth (fourfold increase in tumour doubling time) as well as metastasis.
  
  
  
  The anti-tumour activity of LIVP-GFP is a result of direct oncolysis of tumour cells in case of melanoma B-16 because the virus effectively replicates and destroys these cells, and virus-mediated activation of the host immune system followed by immunologically mediated destruction of of tumour cells in case of lymphosarcoma RLS-40. Thus, the recombinant vaccinia virus LIVP-GFP is able to inhibit the growth of malignant cells with the MDR phenotype and tumour metastasis when administered in the early stages of tumour development.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev ave., Novosibirsk, 630090, Russian Federation.
authors.forename: Elena P
authors.initials: EP
authors.lastname: Goncharova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev ave., Novosibirsk, 630090, Russian Federation.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Ruzhenkova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev ave., Novosibirsk, 630090, Russian Federation.|Department of Biochemistry, Biocenter, University of Wuerzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Petrov
authors.affiliation: Institute of Cytology and Genetics SB RAS, Novosibirsk, Russian Federation.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Shchelkunov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev ave., Novosibirsk, 630090, Russian Federation. marzen@niboch.nsc.ru.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zenkova
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003588:Cytopathogenic Effect, Viral; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007109:Immunity; D007267:Injections; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D050504:Oncolytic Viruses / Q000502:physiology*; D010641:Phenotype; D014616:Vaccinia virus / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; D049452:Green Fluorescent Proteins
keywords: Cancer; Human and murine cancer cells; Immunotherapy; Interleukin IL-6; Melanoma B16; Multiple drug resistance; Oncolytic action; Vaccinia virus; Virotherapy