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Retinole Acid and Interferon a Act Synergistically as Antiangiogenic and Antitumor Agents against Human Head and Neck Squamous Cell Carcinoma1

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy in which multiple independent lesions develop over time throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this neoplasm must include a chemopreventive arm to hold premalignant lesions in check, a role well-suited to antiangiogenic agents. Retinole acid (RA) and interferon a (IFN-a), drugs with known biological activity against HNSCC when used individually, are also inhibitors of angiogenesis. Here we show that they are remarkably synergistic antiangiogenic agents able to inhibit both the growth and the neovascularization of HNSCC injected into the floor of the mouth of nude mice. The mechanism of action of these drugs as antiangiogenic agents was 2-fold. They decreased the angiogenic activity of the tumor cells, and they caused the endothelial cells to become refractory to inducers of angiogen esis. When tumor cells were treated in vitro with IFN-a A/D, there was a dramatic drop in their secretion of interleukin-8, the major angiogenic factor produced by these tumors. When combined with RA, which causes tumor cells to secrete an inhibitor of angiogenesis, there was a synergistic inhibition of both tumor cell growth and secreted angiogenic activity. The combination of RA and IFN-a also acted synergistically on endothelial cells by reducing their responsiveness to both interleukin-8 and tumor conditioned media. Doses of each drug could be reduced by two logs without loss of activity. When animals bearing human HNSCC tumor cells were treated systemically with a combination of RA and IFN-a A/D at doses that were ineffective when used alone, dramatic decreases in both tumor growth and tumor angiogenesis were seen. These data suggest that the use of antiangiogenic mixtures may be a particularly effective way to design future chemoprevention protocols against HNSCC. endometrial carcinoma, and treat ment of advanced stages of squamous cell carcinoma of the skin, esophagus, cervix, vulva, penis, and head and neck. This report looks toward the long-term use of RA and IFN-a together in a chemopreventive setting that would depend primarily on their antiangiogenic activities. It is shown that both agents act on HNSCC tumor cells to limit their ability to stimulate angiogenesis as well as on microvascular endothelial cells to prevent their response to angiogenic factors. Dramatic synergism was seen between these agents both against tumor cells and the normal endothelial cells in vitro. In vivo, they reduced angiogenesis and growth of HNSCC tumor cells, suggesting that their use in combination could be of significant benefit in the long-term chemoprevention of these aggressive neo plasms.