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Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo

Gene Therapy volume 10, pages 434–442 (2003)Cite this article

An Erratum to this article was published on 08 September 2003

Abstract

To accomplish efficient nonviral gene therapy against prostate cancer (PC), Epstein–Barr virus (EBV)-based plasmid vectors containing EBNA1 gene and oriP were employed and combined with a cationic polymer or cationic lipid. When EBV-plasmid/poly-amidoamine dendrimer complex was injected into PC-3-derived tumors established in severe combined immunodeficiency mice, a considerable expression of marker gene was obtained in the tumors, and the expression level was more than eight-fold higher than that achieved by conventional plasmid vector/dendrimer. Since most PC cells express the apoptotic signal molecule Fas (Apo-1/CD95) on their surface, Fas ligand (FasL) gene was transferred into PC cells to kill the tumor cells. In vitro transfection with pGEG.FasL (an EBV-plasmid with the FasL gene) significantly reduced the viability of PC cells, which subsequently underwent apoptosis. Intratumoral injections of pGEG.FasL into PC induced significant growth suppression of the xenograft tumors, in which typical characteristics of apoptosis were demonstrated by TUNEL staining and electron microscopic observations. When pGEG.FasL transfer was accompanied by systemic administrations of cisplatin, the tumors were inhibited even more remarkably, leading to prolonged survival of the animals. FasL gene transfection by means of EBV-based plasmid/cationic macromolecule complexes may provide a practical therapeutic strategy against PC.

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Acknowledgements

We would like to thank Dr Shin Yonehara (Institute for Virus Research, Kyoto University) for kindly providing us with the human Fas ligand gene and Dr Jun-ichi Miyazaki (Department of Nutrition and Physiological Chemistry, Osaka University Medical School) for providing the CAG promoter. This research was supported by a Grant-in-Aid from the Japanese Ministry of Education, Science and Culture (No. 13470339).

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Author notes

  1. O Mazda

    Present address: Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15213, USA

Authors and Affiliations

  1. Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    H Nakanishi, M Nakao, Y Mizutani, A Kawauchi & T Miki

  2. Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    O Mazda, E Satoh, H Asada, T Kishida, M Kita & J Imanishi

  3. Laboratory of Electron Microscopy, Kyoto Prefectural University of Medicine, Kyoto, Japan

    H Morioka

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Nakanishi, H., Mazda, O., Satoh, E. et al. Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo. Gene Ther 10, 434–442 (2003). https://doi.org/10.1038/sj.gt.3301912

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