title: Transferrin lipoplex-mediated suicide gene therapy of oral squamous cell carcinoma in an immunocompetent murine model and mechanisms involved in the antitumoral response.
abstract: Suicide gene therapy has been used for the treatment of a variety of cancers. We reported previously the in vitro efficacy of the Herpes Simplex Virus Thymidine kinase (HSV-tk)/ganciclovir (GCV) system to mediate cytotoxicity in oral squamous cancer cells, using transferrin (Tf)-lipoplexes, prepared from cationic liposomes composed of 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP) and cholesterol. In the present study, we evaluated the antitumoral efficacy mediated by this lipoplex formulation in two suicide gene therapy strategies, HSV-tk/GCV and cytosine deaminase (CD)/5-fluorocytosine (5-FC), using a syngeneic, orthotopic murine model for head and neck squamous cell carcinoma. The cellular and molecular events associated with the antitumoral response elicited by both the therapeutic approaches were investigated by analyzing tumor cell death, tumor-infiltrating immune cells and tumor cytokine microenvironment. Significant tumor reduction was achieved upon intratumoral delivery of HSV-tk or CD genes mediated by Tf-lipoplexes, followed by intraperitoneal injection of GCV or 5-FC, respectively. Enhanced apoptosis, the recruitment of NK cells, CD4 and CD8 T-lymphocytes and an increase in the levels of several cytokines/chemokines were observed within the tumors. These observations suggest that suicide gene therapy with lipoplexes modifies the tumor microenvironment, and leads to the recruitment of immune effector cells that can act as adjuvants in reducing the tumor size.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Neves
authors.forename: H
authors.initials: H
authors.lastname: Faneca
authors.forename: S
authors.initials: S
authors.lastname: Bertin
authors.forename: K
authors.initials: K
authors.lastname: Konopka
authors.forename: N
authors.initials: N
authors.lastname: Düzgüneş
authors.forename: V
authors.initials: V
authors.lastname: Pierrefite-Carle
authors.forename: S
authors.initials: S
authors.lastname: Simões
authors.forename: M C
authors.initials: MC
authors.lastname: Pedroso de Lima
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D002784:Cholesterol / Q000737:chemistry / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005437:Flucytosine / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics / Q000276:immunology*; D014168:Transferrin; D014764:Viral Proteins / Q000235:genetics
chemical_list: D000963:Antimetabolites; D000998:Antiviral Agents; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D014168:Transferrin; D014764:Viral Proteins; D002784:Cholesterol; D005437:Flucytosine; D013937:Thymidine Kinase; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane; D015774:Ganciclovir