Gene expression and antitumor effects following direct interferon (IFN)-γ gene transfer with naked plasmid DNA and DC-chol liposome complexes in mice

T. Nomura, K. Yasuda, T. Yamada, S. Okamoto, R. I. Mahato, Y. Watanabe, Y. Takakura, M. Hashida

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Gene expression was assessed in three types of mouse solid tumors after direct injection of naked plasmid DNA encoding the luciferase gene (pCMV-Luc) and its DC-chol liposome complexes. Intratumoral injection of 5 or 100 μg naked pCMV-Luc into subcutaneously inoculated mouse colon tumor (CT-26), fibrosarcoma (MCA-15) and bladder carcinoma (MBT-2) resulted in significant gene expression. A DC-chol liposome formulation (5 μg pCMV-Luc complexed with 25 μg DC-chol liposome) showed lower level of gene expression in the tumor models. Based on the results using the reporter gene, we examined the antitumor effect after direct interferon-γ (IFN-γ) gene transfer into CT-26 tumors. A significant IFN-γ production and growth inhibition were obtained following direct intratumoral injection of IFN-γ gene with naked plasmid DNA (pCMV-Muγ). Interestingly, pCMV-Muγ/DC-chol liposome complexes exhibited more pronounced growth inhibitory effect despite lower IFN-γ production. Induction of CT-26 specific anti-tumor immunity by IFN-γ gene transfer was confirmed by rejection of a CT-26 tumor challenge in the mice showing complete regression of CT-26 tumors after both treatments. Further analysis demonstrated that a significant cDNA-independent induction of IFN-β and TNF-α occurred following injection with the liposome complexes, suggesting a nonspecific suppressive effect on CT-26 tumor growth by these cytokines. Thus, the present study has demonstrated that tumor tissue might be a promising target for direct IFN-γ gene transfer with plasmid-based nonviral vectors. It is also suggested that immunomodulatory effects by various cytokines could be involved in antitumor effects after direct intratumoral injection of plasmid DNA formulations.

Original languageEnglish (US)
Pages (from-to)121-129
Number of pages9
JournalGene Therapy
Volume6
Issue number1
DOIs
StatePublished - Jan 1999

Keywords

  • DC-chol liposome
  • Gene therapy
  • Interferon-γ
  • Intratumoral injection
  • Naked plasmid DNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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