Inhibition of angiogenesis and vascular tumor growth by interferon-producing cells -: A gene therapy approach

We developed an in vivo gene therapy approach to characterize and optimize the anti-angiogenic activity of class I interferons (IFNs), using packaging cell lines producing an amphotropic LXSN-based retrovirus expressing either IFN-alpha 1 (alpha 1Am21), IFN-beta (beta Am12) murine cDNAs, or the vector alone (neoAm12). Pretreatment of endothelial-like Eahy926 cells in vitro with conditioned media (CM) from alpha 1Am12 or beta Am12 cells for 48 hours significantly inhibited their migration and invasion as compared to neoAm12-CM-treated cells. beta Am12-CM also inhibited the formation of capillary-like structures on Matrigel by EAhy926 cells. In vivo, inclusion of the beta Am12 cells strongly inhibited, and alpha 1Am12 partially inhibited, the angiogenic response in the Matrigel sponge model in both immune-competent and athymic nude mice. Electron microscopy showed a reduction of host cell infiltration in alpha 1Am12- and beta Am12-containing sponges and reduction of invading tubular clefts of host cells as compared to controls. Finally, inoculation of either alpha 1Am12 or beta Am12 cells (10%) along with a highly angiogenic Kaposi's sarcoma cell Line (90%) resulted in a powerful reduction of tumor growth in nude mice in vivo, as did infection with the interferon-alpha-producing retroviruses. These data suggest that a gene therapy approach using class I interferons can effectively inhibit tumor angiogenesis and growth of vascular tumors.