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Long-lasting gene expression by particle-mediated intramuscular transfection modified with bupivacaine: combinatorial gene therapy with IL-12 and IL-18 cDNA against rat sarcoma at a distant site

Cancer Gene Therapy volume 10, pages 318–329 (2003)Cite this article

Abstract

The immune response is modulated by genetic adjuvants using plasmid vectors expressing cytokines. Skeletal muscle can express a foreign gene intramuscularly administered via a needle injection, and the potential of muscle as a target tissue for somatic gene therapy in treating cancer has been explored. In the present study, we investigated the efficacy of particle-mediated intramuscular transfection modified with a local anesthetic agent, bupivacaine, on luciferase and green fluorescent protein. The results indicate that these proteins are more efficiently expressed and persist longer in muscle modified in this way compared with the needle-injection method. Using an established rat sarcoma model, particle-mediated intramuscular gene-gun therapy with a combination of IL-12 and IL-18 cDNA was conducted. Growth of the distant sarcoma was significantly inhibited by particle-mediated intramuscular combination gene therapy, and the survival rate was also improved. Furthermore, the combination gene-gun therapy maintained significant levels of interferon-γ and induced a high activity of tumor-specific cytotoxic T lymphocytes. These results suggest that the sustained local delivery of IL-12 and IL-18 cDNA using intramuscular gene-gun therapy modified with bupivacaine can induce long-term antitumor immunity, and can provide the great advantage of inhibiting the disseminated tumor.

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Acknowledgements

We thank Dr T Osumi (Himeji Institute of Technology, Hyogo, Japan) for donating a GFP plasmid, phGFP-105-C1; Dr S Wolf (the Genetic Institute, Cambridge, MA) for donating a murine IL-12 expression plasmid, pCAGGS-IL-12, Dr K Oshikawa (Jichi Medical School, Tochigi, Japan) for donating mouse pro-IL-18 and ICE plasmids), and Dr Y Matsumoto (Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan) for donating the OX35 and OX8 hybridoma cells. We greatly appreciate the skillful technical assistance of Ms Kyoko Okamoto and Ms Noriko Hayashi. This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Division of Organ Replacement Research and Molecular Immunology, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, 329-0498, Tochigi, Japan

    Takashi Ajiki, Takashi Murakami, Yoji Hakamata, Jun Wang, Seiichiro Inoue & Eiji Kobayashi

  2. Department of Orthopediatrics, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, 329-0498, Tochigi, Japan

    Takashi Ajiki, Yusei Kariya & Yuichi Hoshino

  3. Department of Dermatology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, 329-0498, Tochigi, Japan

    Takashi Murakami, Yukiko Kobayashi, Mamitaro Ohtsuki & Hidemi Nakagawa

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Ajiki, T., Murakami, T., Kobayashi, Y. et al. Long-lasting gene expression by particle-mediated intramuscular transfection modified with bupivacaine: combinatorial gene therapy with IL-12 and IL-18 cDNA against rat sarcoma at a distant site. Cancer Gene Ther 10, 318–329 (2003). https://doi.org/10.1038/sj.cgt.7700575

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