Combined antiangiogenic therapy is superior to single inhibitors in a model of renal cell carcinoma.

Abstract

PURPOSE: Similar to cytotoxic drugs, a combination of antiangiogenic factors may lead to an improved treatment response and minimize resistance by targeting different pathways. Therefore, we investigated the effects of a combination of endogenous inhibitors using endostatin, soluble neuropilin-1 and thrombospondin-2 in a renal cell carcinoma model. MATERIALS AND METHODS: Microencapsulated porcine aortic endothelial cells producing endostatin, soluble neuropilin-1 or thrombospondin-2 were tested in vitro and in a murine renal cell carcinoma alone or as a combination of the all 3 factors. Renca cells were applied subcutaneously for local therapy or injected intravenously in a metastatic model. RESULTS: Factors released from microbeads inhibited endothelial cell function but did not affect tumor cell proliferation in vitro. In vivo tumor growth was inhibited similarly by each angiogenic inhibitor alone (0.17, 0.18 and 0.18 gm in endostatin, soluble neuropilin-1 and thrombospondin-2 treated mice vs 1.3 gm in controls). The combination of all 3 inhibitors further decreased tumor weight (0.03 gm). In the metastatic model treatment with angiogenic inhibitors induced a significant reduction in the size and number of lung metastases with additive effects when factors were used in combination. CONCLUSIONS: The combination of angiogenic inhibitors was superior to single factors, suggesting additive activity. These data support the strategy of combining angiogenic inhibitors to accomplish a complete angiogenic blockade.