Induction of endogenous interferon by superinduction or gene transfection and its anti-tumor activity toward malignant glioma

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Human malignant gliona is one of the most formidable neoplases arising in the brain, and patients afflicted have an average survival time of less than two years. Since malignant gliona invades aggressively into normal brain tissue and tends to disseminate into the subarachnoid space via the cerebro-spinal fluid, surgical resection and/or radiation cannot be expected to be successful. To cure the patient with a malignant brain tumor requires targeting therapy which selectively kills the tumor cells without any damage to normal cells. For this purpose, we have been studying the targeting of cytotoxic agents to glioma cells by using liposomes and a monoclonal antibody(MCA). We entrapped the HuIFN-betza gene inserted in a eukaryotic expression vector (pSV2IFN-beta) into novel liposomes having positive charge on their surface, and found that our liposome-mediated transfer of the gene to cultured glioma cells brought about the production of HuIFN-beta in the cells followed by their growth inhibition. When the plasmid-containing liposomes were coupled with G-22, an MCA against a glioma-associated surface antigen, production of HuIFN-beta in the cells was increased and the growth inhibition of the glioma cells became complete. Furthermore, we found by in vitro experimentation that production of HuIFN-beta in the cells transfected with the gene could be increased by treatment of the cells with tumor necrosis factor-alpha (TNF-alpha) prior to the transfection and that the cells completely disappeared by 9 days after the transfection. Human glioma subcutaneously transplanted into nude mice could be killed completely if the mice were given TNF-alpha prior to the gene transfection. Thus the gate to gene therapy for brain tumors has been opened.