Effects of the novel alpha(v) integrin antagonist SM256 and cis-platinum on growth of murine squamous cell carcinoma PAM LY8

Increased density of proliferating and migrating tumor cells and neovascula r endothelial cells has been associated with tumor progression and poor pro gnosis in patients with squamous cell carcinoma (SCC). Tumor and neovascula r endothelial cells in squamous cell carcinoma have been reported to expres s integrin heterodimers containing the alpha(v) subunit, which binds to vit ronectin and other extracellular matrix proteins that contain the amino aci d recognition sequence Arg-Gly-Rsp (RGD). In the present study, we examined the effect of the novel non-peptide alpha(v) integrin antagonist SM256 on growth of SCC line PAM LY8 in BALB/c SCID mice, and determined whether SM25 6 has direct inhibitory effects on growth of murine endothelial and PAM LY8 SCC cells in vitro. SM256 inhibits cell adhesion of murine cells expressin g alpha(v)beta(3) and alpha(v)beta(5) integrins in vitro with an IC50 of 35 nM and 30 nM, respectively. Growth of PAM LY8 tumors in vivo was inhibited with 14-day continuous administration of SM256 by subcutaneous osmotic dif fusion pump, during which a mean serum concentration of 56 nM was detected. While both murine aortic endothelial cells and PAM LY8 were found to expre ss alpha(v) integrins by fluorescence cytofluorometry, SM256 at 50 nM in MT T assay completely inhibited growth of endothelial cells, but had no signif icant direct effect on growth of PAM LY8 cells. We compared the effect on g rowth of PAM LY8 of SM256 infusion versus single agent or combination chemo therapy with a maximally tolerated dose of cis-platinum, which is used as a standard chemotherapy for SCC. When treatment was initiated at either 7 or 21 days following establishment of tumor, 14-day infusion of SM256 had an inhibitory effect on growth that was similar to that obtained with single d ose cis-platinum, but no additive effect of concurrent therapy with SM256 a nd cis-platinum was observed. These results demonstrate the activity and fe asibility of use of alpha(v) antagonists such as SM256 for therapy of SCC.