title: The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model.
abstract: Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.
authors.affiliation: Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Puig-Saus
authors.affiliation: 1] Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain [2] Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Laborda
authors.affiliation: Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-García
authors.affiliation: Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cascalló
authors.affiliation: Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Moreno
authors.affiliation: Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Alemany
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D006224:Cricetinae; D017931:DNA Primers / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005453:Fluorescence; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008647:Mesocricetus; D051379:Mice; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000379:methods*; D021382:Protein Sorting Signals / Q000235:genetics*; D018709:Statistics, Nonparametric; D057074:Virus Release / Q000187:drug effects / Q000502:physiology*; D000093542:Gemcitabine
chemical_list: D017931:DNA Primers; D021382:Protein Sorting Signals; D003841:Deoxycytidine; D000093542:Gemcitabine