Eradication of p53-mutated head and neck squamous cell carcinoma xenografts using nonviral p53 gene therapy and photochemical internalization.
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.
Centre Alexis Vautrin, EA 3452 Faculté de Pharmacie, Université Henri Poincaré, 54511 Vandoeuvre les Nancy, France.
Alioune
A
Ndoye
Gilles
G
Dolivet
Anders
A
Høgset
Agnès
A
Leroux
Alexandre
A
Fifre
Patrick
P
Erbacher
Kristian
K
Berg
Jean-Paul
JP
Behr
François
F
Guillemin
Jean-Louis
JL
Merlin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009154:Mutation; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011094:Polyethyleneimine / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017319:Photosensitizing Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011094:Polyethyleneimine; D008156:Luciferases; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases