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Effects of Angiostatin Gene Transfer on Functional Properties and in Vivo Growth of Kaposi’s Sarcoma Cells¹

Istituto Nazionale per la Ricerca sul Cancro, Biotechnology Section-Padova, 35128 Padova, Italy [S. I.]; Modulo di Progressione Neoplastica [M. M., D. M. N.] and Laboratorio di Biologia Molecolare, 16132 Genova, Italy [A. A.]; Department of Oncology and Surgical Sciences, University of Padova, 35128 Padova, Italy [S. I., E. G., W. H., L. C-B.]; Advanced Biotechnology Center, 16132 Genova, Italy [F. C., S. M., L. S.]; Departments of Oncology, Biology, and Biotechnology, University of Genova, 16132 Genova, Italy [L. S.]; and Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, S171 76 Stockholm, Sweden [Y. C.]

Gene transfer delivery of endogenous angiogenesis inhibitors such as angiostatin would circumvent problems associated with long-term administration of proteins. Kaposi’s sarcoma (KS), a highly vascular neoplasm, is an excellent model for studying tumor angiogenesis and antiangiogenic agent efficacy. We investigated the effects of angiostatin gene transfer in in vitro and in vivo models of KS-induced neovascularization and tumor growth. A eukaryotic expression plasmid and a Moloney leukemia virus-based retroviral vector for expression of murine angiostatin were generated harboring the angiostatin cDNA with cleavable leader signals under the control of either the strong cytomegalovirus promoter/enhancer or the Moloney leukemia virus long terminal repeat. Angiostatin secretion was confirmed by radioimmunoprecipitation and Western blot analysis. Supernatants of angiostatin-transfected cells inhibited endothelial cell migration in vitro. Stable gene transfer of the angiostatin cDNA by retroviral vectors in KS-IMM cells resulted in sustained angiostatin expression and delayed tumor growth in nude mice, which was associated with reduced vascularization. These findings suggest that gene therapy with angiostatin might be useful for treatment of KS and possibly other highly angiogenic tumors.

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