1. Academic Validation
  2. Combined suicide gene therapy for pancreatic peritoneal carcinomatosis using BGTC liposomes

Combined suicide gene therapy for pancreatic peritoneal carcinomatosis using BGTC liposomes

  • Cancer Gene Ther. 2004 Jan;11(1):16-27. doi: 10.1038/sj.cgt.7700628.
Amor Hajri 1 Séverine Wack Pierre Lehn Jean-Pierre Vigneron Jean-Marie Lehn Jacques Marescaux Marc Aprahamian
Affiliations

Affiliation

  • 1 INSERM U375, IRCAD, 1 place de l'Hôpital, BP 426, 67091 Strasbourg, France. amor.hajri@ircad.u-strasbg.fr
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142996
    Cationic Lipid