title: TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer.
abstract: We have explored a unique combination therapy for metastatic colorectal cancer. This strategy combines a potent and new oncolytic poxvirus expressing a membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or TNFSF10) and oxaliplatin (Ox) chemotherapy. We hypothesized that TRAIL expression would increase the efficacy of the oncolytic poxvirus, and that the therapeutic efficacy would be further enhanced by combination with chemotherapy. The cytotoxicity to cancer cells by Ox, oncolytic vaccinia virus (VV) and trail gene-armed VV alone or in combination was tested in vitro. The trail gene armed oncolytic VV-expressed high levels of TRAIL in infected cancer cells and had greater potency as a cytotoxic agent compared with the parent VV. Ox alone exerted concentration-dependent cytotoxicity. In vitro, the combination of the two agents applied at suboptimal concentrations for individual therapy displayed synergy in inducing cancer cells into enhanced levels of apoptosis/necrosis. Western blot analyses were consistent with the notion that TRAIL induced cancer cell death mainly through apoptosis, whereas Ox and vJS6 induced cell death more through non-apoptotic death pathways. In two aggressive colorectal carcinomatosis models derived from human HCT116 and murine MC38 cells, the combination therapy displayed synergistic or additive antitumor activity and prolonged the survival of the tumor-bearing mice compared with either Ox chemotherapy or vvTRAIL-mediated oncolytic gene therapy alone. This combination strategy may provide a new avenue to treating peritoneal carcinomatosis and other types of metastases of colorectal cancer.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Ziauddin
authors.forename: Z S
authors.initials: ZS
authors.lastname: Guo
authors.forename: M E
authors.initials: ME
authors.lastname: O'Malley
authors.forename: F
authors.initials: F
authors.lastname: Austin
authors.forename: P J
authors.initials: PJ
authors.lastname: Popovic
authors.forename: M A
authors.initials: MA
authors.lastname: Kavanagh
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Sathaiah
authors.forename: P
authors.initials: P
authors.lastname: Thirunavukarasu
authors.forename: B
authors.initials: B
authors.lastname: Fang
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
authors.forename: D L
authors.initials: DL
authors.lastname: Bartlett
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D011212:Poxviridae; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000077150:Oxaliplatin