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Systemic Inhibition of Tumor Growth and Angiogenesis by Thrombospondin-2 Using Cell-based Antiangiogenic Gene Therapy¹

Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129 [M. S., T. H., K. M., B. L-A., M. D.]; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston 02114 [A. E. S., J. P. V.]; and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston 02215 [L. F. B.] Massachusetts

Recent studies indicate that continuous administration improves the antitumoral efficacy of angiogenesis inhibitors, as compared with intermittent dosing, suggesting a potential role of gene therapy in antiangiogenic tumor therapy. We established a tissue-engineered implant system for the continuous in vivo production of thrombospondin-2 (TSP-2), a potent endogenous inhibitor of tumor growth and angiogenesis. Fibroblasts were retrovirally transduced to overexpress TSP-2 and were seeded onto biodegradable polymer scaffolds. After transplantation into the peritoneal cavity of nude mice, bioimplants maintained high levels of TSP-2 secretion over extended time periods, resulting in increased levels of circulating TSP-2. Bioimplant-generated TSP-2 potently inhibited tumor growth and angiogenesis of human squamous cell carcinomas, malignant melanomas, and Lewis lung carcinomas that were implanted at a distant site. These results provide the first proof-of-principle for the feasibility and therapeutic efficiency of systemic, cell-based antiangiogenic gene therapy using biodegradable polymer grafts for the treatment of cancer.

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