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Cellular and molecular events associated with the antitumor response induced by the cytosine deaminase/5-fluorocytosine suicide gene therapy system in a rat liver metastasis model

Cancer Gene Therapy volume 14, pages 858–866 (2007)Cite this article

Abstract

The bacterial cytosine deaminase (CD) gene converts the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil. We have previously shown, in a rat liver metastasis model from colon carcinoma, that intratumoral injection of a CD-expressing plasmid into the animals followed by 5-FC treatment results in the regression of the treated tumor as well as distant uninjected tumors. The aim of this study was to further analyze the mechanisms associated with tumor regression induced upon application of suicide CD/5-FC strategy. Tumor regression was associated with an increased apoptosis, the recruitment of natural killer cells, CD4- and CD8 T lymphocytes within the tumors and an increased expression of several cytokines/chemokines mRNAs. These data indicate that the CD/5-FC suicide strategy is associated with the triggering of cellular and molecular events leading to an efficient antitumor immune response involving both innate and acquired immunity.

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Abbreviations

CD:

cytosine deaminase

Chol:

cholesterol

DOTAP:

1,2-dioleoyl-3-(trimethylammonium) propane

5-FC:

5-fluorocytosine

5-FU:

5-fluorouracil

Lt-β:

lymphotactin-β

MCP-1:

monocyte chemoattractant protein-1

NK:

natural killer

RPA:

RNase protection assay

TUNEL:

terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling

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Acknowledgements

We thank Dr Pascal Staccini (Département Informatique Médicale, Faculté de Médecine, Nice) for statistical analysis of the results. We also thank Agnès Loubat, Vincent Balaya, Olivier Camuzard and Vincent Saury for expert technical assistance. We would like to dedicate this work to Bernard Rossi, Head of the Laboratory, who deceased in May 2006. This work was supported by the Institut National de la Santé et de la Recherche Médicale, Fondation de l'Avenir, France Cancer and Association pour la Recherche sur le Cancer and by the Portuguese Foundation for Science and Technology (Grants SFRH/BD/8711/2002 and POCTI/CVT/44854/2002).

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Author notes

  1. S Bertin and S Neves: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, Unité 638, Nice, France

    S Bertin, A Gavelli, P Baqué, N Brossette & V Pierrefite-Carle

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

    S Bertin, A Gavelli, P Baqué, N Brossette & V Pierrefite-Carle

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

    S Neves, S Simões & M C Pedroso de Lima

  4. Service de Chirurgie Générale et Digestive, Centre Hospitalier Princesse Grace, Monaco

    A Gavelli

  5. Service de Chirurgie d'Urgence, Hôpital St Roch, Nice, France

    P Baqué

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

    S Simões

  7. Department of Biochemistry, University of Coimbra, Coimbra, Portugal

    M C Pedroso de Lima

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  1. S Bertin
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Correspondence to V Pierrefite-Carle.

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Bertin, S., Neves, S., Gavelli, A. et al. Cellular and molecular events associated with the antitumor response induced by the cytosine deaminase/5-fluorocytosine suicide gene therapy system in a rat liver metastasis model. Cancer Gene Ther 14, 858–866 (2007). https://doi.org/10.1038/sj.cgt.7701075

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