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Transferrin lipoplex-mediated suicide gene therapy of oral squamous cell carcinoma in an immunocompetent murine model and mechanisms involved in the antitumoral response

Cancer Gene Therapy volume 16, pages 91–101 (2009)Cite this article

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.

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Acknowledgements

Sílvia Neves is the recipient of a fellowship from Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/8711/2002). This work was supported by grants from FCT (POCTI/CVT/44854/2002) and (PTDC/BIO/65627/2006).

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Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    S Neves, H Faneca, S Simões & M C Pedroso de Lima

  2. INSERM, Unité 638, Nice, France

    S Bertin & V Pierrefite-Carle

  3. Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France

    S Bertin & V Pierrefite-Carle

  4. Department of Microbiology, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco, CA, USA

    K Konopka & N Düzgüneş

  5. Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    S Simões

  6. Department of Biochemistry, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal

    M C Pedroso de Lima

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Neves, S., Faneca, H., Bertin, S. et al. Transferrin lipoplex-mediated suicide gene therapy of oral squamous cell carcinoma in an immunocompetent murine model and mechanisms involved in the antitumoral response. Cancer Gene Ther 16, 91–101 (2009). https://doi.org/10.1038/cgt.2008.60

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