Systemic Administration of Naked DNA Encoding Interleukin 12 for the Treatment of Human Papillomavirus DNA-Positive Tumor

Abstract

Interleukin 12 (IL-12) is one of the most effective and promising cytokines for cancer therapy. Its therapeutic effects have been demonstrated in a variety of tumors in animal models when it is administrated locally or systemically. We describe here a systemic delivery of naked murine IL-12 (mIL-12) gene in vivo. Dose-dependent systemic production of mIL-12, with a serum level up to approximately 20μg/ml, was observed 24 hr after systemic gene delivery. The apparent half-life in the circulation was about 5 hr. The result of a bioactivity assay (in vitro interferon γ [IFN-γ] release) indicated that the gene product in mice was as active as the purified recombinant murine IL-12 protein (rmIL-12). The circulating mIL-12 activated natural killer cells and stimulated IFN-γ production in vivo. A single administration of mIL-12 gene resulted in prominent regression of established subcutaneous tumor in a human papillomavirus (HPV) DNA-positive tumor model (TC-1) in C57BL/6J mice. The antitumor effect of the single gene dose was comparable to repeated intraperitoneal administration of rmIL-12 (0.5 μg/day for consecutive 5 days). This systemic gene delivery is simple, economical, and highly efficient for the production of large amounts of cytokine in vivo. With this gene delivery method, we have demonstrated the therapeutic potential of IL-12 for the treatment of HPV DNA-positive tumor and the usefulness of the systemic gene delivery for assessing the therapeutic effect of a candidate gene.