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_vß₃ Integrin Antagonist S247 Decreases Colon Cancer Metastasis and Angiogenesis and Improves Survival in Mice¹

Departments of Cancer Biology [N. R., W. L., F. F., O. S., C. D. B., G. E. G., L. M. E.] and Surgical Oncology [S. A. A., A. A. P., L. M. E.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Oncology Pharmacology, Discovery Research, Pharmacia Corporation [M. A. N., W. F. W.], St. Louis, Missouri 63198

Members of the integrin family influence several aspects of tumor progression and metastasis, including cell survival, proliferation, and angiogenesis. Specific integrins such as _vß₃ and _vß₅ are involved in regulating endothelial cell function, and thus angiogenesis. We evaluated the effect of the _vß₃/_vß₅ integrin antagonist S247 on the growth and angiogenesis of colon cancer liver metastases in an orthotopic murine model. Murine colon cancer cells were injected into the spleens of BALB/c mice to produce liver metastases. On day 7, miniature osmotic pumps were implanted into the subcutis to continuously infuse either saline or 70 mg/kg/day S247. All mice were sacrificed when control mice became moribund. Mice that received S247 developed significantly fewer liver metastases than did controls (P < 0.05). Using the same model, a subsequent survival study was performed. Mice were sacrificed when moribund as determined by an observer blinded to the treatment given. Treatment with S247 significantly prolonged overall survival (P < 0.05). Interestingly, primary tumors in the spleen were the cause of death in the S247-treated group as S247 appeared to have little effect on these tumors. Immunohistochemical staining demonstrated a significant reduction of vessels in liver metastases of S247-treated mice (P < 0.001), a significant increase in endothelial cell apoptosis (P < 0.05), and a significant decrease in pericyte coverage (P < 0.0001). To determine the role of S247 on angiogenesis, we examined the effect of S247 in vitro on human umbilical vein endothelial cells (HUVECs) and human vascular smooth muscle cells (hVSMCs). The addition of S247 to HUVECs and hVSMCs growing on vitronectin-coated flasks and in Matrigel significantly impaired cell growth and colony formation, respectively (P < 0.05). Furthermore, S247 completely inhibited the attachment of HUVECs and hVSMCs and increased apoptosis by six- to 9fold compared with controls. In in vitro invasion assays, S247-treated cells demonstrated decreased migration (P < 0.05). In conclusion, S247 demonstrated significant antimetastatic and antiangiogenic activity and impaired both endothelial and hVSMC/pericyte function in vitro and in vivo. The use of agents such as integrin antagonists that target multiple cell types involved in angiogenesis may be a more effective method of inhibiting angiogenesis than agents targeting only the endothelial cells.

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