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

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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 antitumor 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.