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Combined suicide gene therapy for pancreatic peritoneal carcinomatosis using BGTC liposomes

Cancer Gene Therapy volume 11, pages 16–27 (2004)Cite this article

Abstract

Peritoneal dissemination is a common end-stage complication of pancreatic cancer for which novel therapeutic modalities are actively investigated, as there is no current effective therapy. Thus, we evaluated, in a mouse model of pancreatic peritoneal carcinomatosis, the therapeutic potential of a novel nonviral gene therapy approach consisting of bis-guanidinium-tren-cholesterol (BGTC)-mediated lipofection of a combined suicide gene system. Human BxPC-3 pancreatic cells secreting the carcinoembryonic antigen (CEA) tumor marker were injected into the peritoneal cavity of nude mice. After 8 days, intraperitoneal (i.p.) lipofection was performed using BGTC/DOPE cationic liposomes complexed with plasmids encoding the two prodrug-activating enzymes Herpes Simplex Virus thymidine kinase and Escherichia coli cytosine deaminase, the latter being expressed from a bicistronic cassette also encoding E. coli uracil phosphoribosyltransferase. Administration of the lipoplexes was followed by treatment with the corresponding prodrugs ganciclovir and 5-fluorocytosine. The results presented herein demonstrate that BGTC/DOPE liposomes can efficiently mediate gene transfection into peritoneal tumor nodules. Indeed, HSV-TK mRNA was detected in tumor nodule tissues by semiquantitative reverse transcription-polymerase chain reaction analysis. In addition, green fluorescent protein (GFP) fluorescence and X-gal staining were observed in the peritoneal tumor foci following lipofection of the corresponding EGFP and LacZ reporter genes. These expression analyses also showed that transgene expression lasted for about 2 weeks and was preferential for the tumor nodules, this tumor preference being in good agreement with the absence of obvious treatment-related toxicity. Most importantly, mice receiving the full treatment scheme (BGTC liposomes, suicide genes and prodrugs) had significantly lower serum CEA levels than those of the various control groups, a finding indicating that peritoneal carcinomatosis progression was strongly reduced in these mice. In conclusion, our results demonstrate the therapeutic efficiency of BGTC-mediated i.p. lipofection of a combined suicide gene system in a mouse peritoneal carcinomatosis model and suggest that BGTC-based prodrug-activating gene therapy approaches may constitute a potential treatment modality for patients with peritoneal carcinomatosis and minimal residual disease.

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Acknowledgements

This work was supported in part by grants from the Association pour la Recherche sur le Cancer (ARC, Villejuif, France) and Institut de Recherche sur le Cancer de l'Appareil Digestif (IRCAD, Strasbourg, France).

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Authors and Affiliations

  1. INSERM U375, IRCAD, 1 place de l'Hôpital, Strasbourg, BP 426-67091, Cedex, France

    Amor Hajri, Séverine Wack, Jacques Marescaux & Marc Aprahamian

  2. INSERM U458, Hôpital Robert Debré, 48 boulevard Sérurier, Paris, 75019, France

    Pierre Lehn

  3. Laboratoire de Chimie des Interactions Moléculaires, Collège de France, 11 place Marcelin Berthelot, Paris, 75005, France

    Jean-Pierre Vigneron & Jean-Marie Lehn

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  1. Amor Hajri
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Correspondence to Amor Hajri.

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Hajri, A., Wack, S., Lehn, P. et al. Combined suicide gene therapy for pancreatic peritoneal carcinomatosis using BGTC liposomes. Cancer Gene Ther 11, 16–27 (2004). https://doi.org/10.1038/sj.cgt.7700628

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