Eradication of p53-mutated head and neck squamous cell carcinoma xenografts using nonviral p53 gene therapy and photochemical internalization

Alioune Ndoye; Gilles Dolivet; Anders Høgset; Agnès Leroux; Alexandre Fifre; Patrick Erbacher; Kristian Berg; Jean-Paul Behr; François Guillemin; Jean-Louis Merlin

doi:10.1016/j.ymthe.2006.02.003

Eradication of p53-mutated head and neck squamous cell carcinoma xenografts using nonviral p53 gene therapy and photochemical internalization

Mol Ther. 2006 Jun;13(6):1156-62. doi: 10.1016/j.ymthe.2006.02.003. Epub 2006 Mar 27.

Authors

Alioune Ndoye¹, Gilles Dolivet, Anders Høgset, Agnès Leroux, Alexandre Fifre, Patrick Erbacher, Kristian Berg, Jean-Paul Behr, François Guillemin, Jean-Louis Merlin

Affiliation

¹ Centre Alexis Vautrin, EA 3452 Faculté de Pharmacie, Université Henri Poincaré, 54511 Vandoeuvre les Nancy, France.

PMID: 16564229
DOI: 10.1016/j.ymthe.2006.02.003

Abstract

Photochemical internalization (PCI) technology has been used for PEI-mediated p53 gene transfer in mice bearing head and neck squamous cell carcinoma (HNSCC) xenografts. Using luciferase as a reporter gene, PCI led to a 20-fold increase in transgene expression 48 h after transfection and sustained transgene expression for 7 days. Therefore, iterative p53 gene transfer was performed by means of a weekly single injection of PEIGlu4/p53 complexes alone or with PCI for 5 (group A) or 7 (group B) weeks. The efficiency of p53 gene therapy was evaluated by following tumor growth and expression of P53-related downstream proteins (P21, MDM2, Bcl2, Bax). Apoptosis induction was evidenced through caspase-3 activation and PARP cleavage. Using PCI, tumor growth inhibition was observed in all transfected animals. Further, successful tumor cure was achieved in 17% (group A) and 83% (group B) of animals. PCI-mediated p53 gene transfer led to higher P53 protein expression that was correlated with induction of Bax and P21 proapoptotic proteins, repression of Bcl2 as well as activation of caspase-3, and cleavage of PARP. The present study demonstrates that PCI enhances the in vivo efficiency of PEI-mediated p53 gene transfer and can be proposed for p53 gene therapy in HNSCC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / genetics
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / therapy*
Caspase 3
Caspases / metabolism
Combined Modality Therapy
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Female
Gene Expression
Gene Transfer Techniques
Genetic Therapy / methods*
Head and Neck Neoplasms / genetics
Head and Neck Neoplasms / therapy*
Humans
Luciferases / genetics
Mice
Mutation*
Photochemotherapy / methods*
Photosensitizing Agents / pharmacology
Poly(ADP-ribose) Polymerases / metabolism
Polyethyleneimine / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein / genetics
bcl-2-Associated X Protein / metabolism

Substances

Cyclin-Dependent Kinase Inhibitor p21
Photosensitizing Agents
Proto-Oncogene Proteins c-bcl-2
Tumor Suppressor Protein p53
bcl-2-Associated X Protein
Polyethyleneimine
Luciferases
Proto-Oncogene Proteins c-mdm2
Poly(ADP-ribose) Polymerases
CASP3 protein, human
Casp3 protein, mouse
Caspase 3
Caspases