title: Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors.
abstract: Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells.
authors.affiliation: Center for Cancer Therapeutics, Ottawa Hospital Research Institute, Ontario, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: MacTavish
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.forename: Baocheng
authors.initials: B
authors.lastname: Huang
authors.forename: Marianne
authors.initials: M
authors.lastname: Stanford
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.forename: Naomi
authors.initials: N
authors.lastname: De Silva
authors.forename: Julie
authors.initials: J
authors.lastname: Cox
authors.forename: John Graydon
authors.initials: JG
authors.lastname: Simmons
authors.forename: Tanya
authors.initials: T
authors.lastname: Guimond
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
authors.forename: Harry
authors.initials: H
authors.lastname: Atkins
authors.forename: Caroline
authors.initials: C
authors.lastname: Breitbach
authors.forename: David
authors.initials: D
authors.lastname: Kirn
authors.forename: Stephen
authors.initials: S
authors.lastname: Thorne
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007107:Immune System; D007372:Interferons / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism; D014616:Vaccinia virus / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D007372:Interferons