title: Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer.
abstract: Metastatic colorectal cancer (CRC) is complex clinical challenge for which there are limited treatment options. Chemotherapy with or without surgery provides moderate improvements in overall survival and quality of life; nevertheless the 5-year survival remains below 30%. Oncolytic vaccinia virus (VV) shows strong anti-tumour activity in models of CRC, however transient delays in disease progression are insufficient to lead to long-term survival. Here we examined the efficacy of VV with oxaliplatin or SN-38 (active metabolite of irinotecan) in CRC cell lines in vitro and VV with irinotecan in an orthotopic model of metastatic CRC. Synergistic improvements in in vitro cell killing were observed in multiple cell lines. Combination therapy was well tolerated in tumour-bearing mice and the median survival was significantly increased relative to monotherapy despite a drug-dependent decrease in the mean tumour titer. Increased apoptosis following in vitro and in vivo combination therapy was observed. In vitro cell cycle analysis showed increases in S-phase cells following infection occurred in both infected and uninfected cell populations. This corresponded to a 4-fold greater increase in apoptosis in the uninfected compared to infected cells following combination therapy. Combination treatment strategies are among the best options for patients with advanced cancers. VV is currently under clinical investigation in patients with CRC and the data presented here suggest that its combination with irinotecan may provide benefit to a subset of CRC patients. Further, investigation of this combination is necessary to determine the tumour characteristics responsible for mediating synergy.
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ottolino-Perry
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Acuna
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Angarita
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: Sellers
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada.
authors.forename: Siham
authors.initials: S
authors.lastname: Zerhouni
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada.
authors.forename: Nan
authors.initials: N
authors.lastname: Tang
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, 67 College St., Toronto, Ontario, M5G 2M1, Canada; Department of Surgery, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario, M5G 1X5, Canada; Department of Surgery, University of Toronto, 149 College St., Toronto, Ontario, M5T 1P5, Canada. Electronic address: amccart@uhnres.utoronto.ca.
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D014616:Vaccinia virus
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin
keywords: Chemotherapy; Combination therapy; Double-deleted vaccinia virus; Metastatic colorectal cancer; Oncolytic virotherapy; Orthotopic tumour model