Novel small molecule alpha v integrin antagonists: Comparative anti-cancerefficacy with known angiogenesis inhibitors

Recent evidence supports the involvement of integrins in angiogenesis: bloc kade of alpha v beta 3 and alpha v beta 5 integrins disrupts angiogenesis l ending to decreased blood vessel formation and hence decreased tumor growth . We hypothesized that av antagonists could inhibit tumor growth in tumor c ells devoid of alpha v beta 3 integr'ns. We evaluated SM256 and SD983, nove l small molecules that are specific av antagonists in mouse models of angio genesis and tumorigenesis, and compared them with standards: TNP470, a fuma gillin analog in the clinic, and flavopiridol, a cell cycle kinase inhibito r. In vitro SM256 was a selective alpha v beta 3 inhibitor with an IC50=4nM , and the affinity of SD983 against the mouse endothelial alpha v beta 3 in tegrin yielded an IC50=2nM and an IC50=54nM against alpha v beta 5. In the mouse Matrigel model of angiogenesis SM256 decreased blood vessel formation (hemoglobin content) with an ED50=0.055 ug/kg/day, tenfold more potent tha n TNP470. SG545, an ester of SD983, decreased blood vessel formation with a n ED50=6 ug/kg/day, while flavopiridol ED50=18 ug/kg/day. In the mouse xeno graft model, using human colon carcinoma RKO cells that do not express alph a v beta 3 but express alpha v beta 5, tumor growth was inhibited by SG545 (10 mg/kg/day) and flavopiridol (5 mg/kg/every other day) 40% and 70%, resp ectively (p<0.05). Although the proliferative index (measured by BrdU incor poration) was not significantly changed with SM256, SG545 or flavopiridol ( 29-32%), the apoptotic index increased significantly (p<0.05) in the SM256 and SG545-treated groups (2.3-2.7%) compared with controls (1.1%), suggesti ng increased cell death contributed to decreased tumor volumes. Neovascular ization decreased with SM256 and SG545 treatment. The data demonstrate that potent selective av antagonists can target endothelial cells, tumor cells, inhibit angiogenesis and inhibit tumor growth.