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In vivo growth inhibitory effect of iterative wild-type p53 gene transfer in human head and neck carcinoma xenografts using glucosylated polyethylenimine nonviral vector

Cancer Gene Therapy volume 9, pages 708–714 (2002)Cite this article

Abstract

Polyethylenimine (PEI) derivatives are polycationic nonviral vectors for gene transfer. Previous results achieved in vitro in head and neck cancer cells demonstrated that glucosylated PEI yields higher gene transfer efficiency and longer transgene expression than unsubstituted PEI. Using glucosylated PEI, p53 gene transfer was successfully achieved with subsequent recovery of P53 protein expression and induction of spontaneous apoptosis. The present study reports in vivo data achieved in human head and neck squamous cell carcinoma xenografted mice. Using biotinylated PEI and histochemistry analysis, the vector was found to diffuse in the proliferating cells of the tumor tissue, sparing necrotic areas. No diffusion was observed inside keratinized area composed of nonproliferating, mature differentiated cells. Using green fluorescent protein (GFP) transfection and fluorescence microscopy, the transgene expression was mainly observed at the periphery of the tumor containing proliferating cells. GFP expression appeared lower inside the tumor depth. Quantitative transgene expression kinetics was then determined using luciferase as reporter gene. The maximal transgene expression was achieved 48 hours after intratumoral injection of glucosylated PEI/DNA complexes. The highest gene transfer efficacy was achieved 48 hours after two intratumoral injection. After transfection of wild-type p53, tumor growth inhibition was observed in tumor-bearing mice receiving intratumoral injection of glucosylated PEI/DNA complexes repeated twice weekly. Tumor growth inhibition was maintained under continuous treatment using the same schedule. In all experiments, no noticeable toxicity was observed. The present results demonstrate the feasibility and the tumor growth inhibition potency of nonviral gene transfer using glucosylated polyethylenimine.

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Acknowledgements

The authors are grateful to E Festor and S Dezan for technical assistance and to D Marius-Leprince for editorial assistance. This study was supported by grants from the French “Ligue Nationale contre le Cancer,” “Pôle Européen de Santé: Région Lorraine, Communauté Urbaine du Grand Nancy” and Alexis Vautrin Cancer Center private research funds.

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Authors and Affiliations

  1. Centre Alexis Vautrin, Avenue de Bourgogne, Vandœuvre-Nancy, France

    Gilles Dolivet, Jean-Louis Merlin, Muriel Barberi-Heyob, Carole Ramacci, R-Michel Parache & François Guillemin

  2. Unité de Chirurgie Cervico-Faciale, Avenue de Bourgogne, Vandœuvre-Nancy, France

    Gilles Dolivet

  3. Laboratoire de Recherche en Oncologie, Avenue de Bourgogne, Vandœuvre-Nancy, France

    Jean-Louis Merlin, Muriel Barberi-Heyob, Carole Ramacci & François Guillemin

  4. PoLyplus-Transfection SA, Faculté de Pharmacie, Illkirch, BP 21, France

    Patrick Erbacher

  5. Service d'Anatomie et de Cytologie Pathologique, Avenue de Bourgogne, Vandœuvre-Nancy, France

    R-Michel Parache

  6. Laboratoire de Chimie Génétique, CNRS UMR 7514, Faculté de Pharmacie, Illkirch, BP 24, France

    Jean-Paul Behr

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  1. Gilles Dolivet
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Correspondence to Jean-Louis Merlin.

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Dolivet, G., Merlin, JL., Barberi-Heyob, M. et al. In vivo growth inhibitory effect of iterative wild-type p53 gene transfer in human head and neck carcinoma xenografts using glucosylated polyethylenimine nonviral vector. Cancer Gene Ther 9, 708–714 (2002). https://doi.org/10.1038/sj.cgt.7700485

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