Electrochemo-gene therapy of Cancer using Epstein Barr virus-plasmid vector ; Intratumoral delivery of Interleukin-12 gene and bleomycin induce therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice

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INTRODUCTION AND OBJECTIVES : Cytotoxic chemotherapy has shown little antitumor activity against carcinomas. Immunotherapy is relatively effective against melanoma. In the present study, we investigated the effectiveness of the combination therapy with Intratumoral delivery of Interleukin (IL) 12 gene using electroporation and intratumoral injection of bleomycin against immuno sensitive melanoma cell line, B 16.METODS : To treat established immuno sensitive melanoma tumors in mice, intratumoral transfer of bleomycin and/or an IL12 expression Epstein-Barr Virus-plasmid vector was performed by means of electroporation.RESULTS : Although either bleomycin alone or the IL12 gene alone significantly suppressed the subcutaneous tumors, the combination therapy drastically improved the therapeutic outcome. Three of eight mice (37.5%) that received both bleomycin and the IL12 gene showed complete remission of the preestablished tumors and rejected subsequent rechallenge with the tumor cells. We also examined whether electrochemo-gene therapy for subcutaneous tumor mass induced suppression of pulmonary metastasis that had been established by intravenous inoculation of the melanoma cells. Although metastatic foci were significantly reduced in number in groups that were given IL12 gene alone or bleomycin plus IL12 gene, it was only the combination therapy that significantly prolonged the mean survival period of the tumor-bearing animals. Natural killer(NK) and cytotoxic T lymphocyte cytolytic activities were markedly enhanced in the mice that received the chemo-gene therapy, while IL12 gene therapy alone partially elevated the NK cytotoxicity.CONCLUSIONS : The present study suggests that the electroporation-mediated delivery of the IL12 gene and bleomycin synergistically elicits innate and adaptive anti-melanoma immune responses, resulting in marked suppression of the treated tumors as well as bystander metastatic lesions.