INTEGRIN ACTIVATION SUPPRESSES ETOPOSIDE-INDUCED DNA STRAND BREAKAGE IN CULTURED MURINE TUMOR-DERIVED ENDOTHELIAL-CELLS

Tumor endothelium is critical for solid tumor growth and is a potentia l site for anticancer drug action, Within 2 h, etoposide caused marked DNA strand breakage in xenograft tumor-derived endothelial cells (TDE Cs), Etoposide-induced DNA breakage was inhibited by culturing TDECs o n gelatin, type IV collagen, laminin, fibronectin, and the integrin li gand hexapeptide, GRGDSP, but not the inactive peptide, GRADSP, It was also inhibited when TDECs were on surfaces coated with antibodies to alpha(5), beta(1), or beta(3) integrin subunits and by clustering inte grins with soluble antibodies. After 8 h with etoposide, TDECs detache d from the monolayer, and 50-kb DNA fragments were seen, Fibronectin i nhibited both processes, Thus, integrins are survival factors for TDEC that inhibit the genotoxicity of etoposide and may influence the sens itivity of tumors to drugs.