Tumor Dormancy Therapy Using Genetically Engineered Drug Delivery System

Makoto Sunamura, Dan G. Duda, Hiromune Shimamura, Fuyuhiko Motoi, Toshimasa Yatsuoka, Kazuhiko Shibuya, Kazunori Takeda and Seiki Matsuno

First Department of Surgery, Tohoku University School of Medicine

Tumor dormancy therapy appears useful in treating cancer, but requires that a patient take medication during control of remnant cancer cells. To overcome this inconvenience to patients, drug delivery using genetically engineered cells has become an alternative. Interleukin-12 is both a key regulator of the immune response, particularly that involving CTL and NK cells, and an antiangiogenesis agent. We report the usefulness of the drug delivery of fibroblasts genetically engineered to secrete this cytokine to control angiogenesis in human pancreatic tumors in NK-depleted SCID mice. We evaluate the antiangiogenesis of soluble VEGF receptor (s-flt1) and brain-specific angiogenesis inhibitor 1 (BAI1). Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12 secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. Neovascularization surrounding the tumor was markedly inhibited where IL-12-secreting fibroblasts were implanted, suppressing tumor growth. Lectin staining in tumor sample sections also showed a significantly reduced number of vessels. The RNA expression of IFN-γ and its inducible antiangiogenic chemokine IP-10 was stimulated in endothelial cells cultured with IL-12. We also found that IL-12 downregulated the expression of endothelial cell mitogens VEGF and bFGF. Antitumor effect and antiangiogenesis of s-flt1 and BAI1 were also demonstrated.

Key words
drug delivery system, tumor dormancy, pancreatic cancer

Reprint requests
Makoto Sunamura 1^ST Department of Surgery, Tohoku University School of Medicine 1-1 Seiryo-cho, Aoba-ku, Sendai, 980-8574 JAPAN

Accepted
December 19, 2000

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