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Integrin Activation Suppresses Etoposide-induced DNA Strand Breakage in Cultured Murine Tumor-derived Endothelial Cells¹

Departments of Pharmacology [D. G. H., J. M. R., R. J. M., C. S. J., J. S. L.] and Otolaryngology [R. A. M., C. S. J.], University of Pittsburgh School of Medicine, and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15261

Tumor endothelium is critical for solid tumor growth and is a potential site for anticancer drug action. Within 2 h, etoposide caused marked DNA strand breakage in xenograft tumor-derived endothelial cells (TDECs). Etoposide-induced DNA breakage was inhibited by culturing TDECs on gelatin, type IV collagen, laminin, fibronectin, and the integrin ligand hexapeptide, GRGDSP, but not the inactive peptide, GRADSP. It was also inhibited when TDECs were on surfaces coated with antibodies to ₅, ß₁, or ß₃ integrin subunits and by clustering integrins with soluble antibodies. After 8 h with etoposide, TDECs detached from the monolayer, and 50-kb DNA fragments were seen. Fibronectin inhibited both processes. Thus, integrins are survival factors for TDEC that inhibit the genotoxicity of etoposide and may influence the sensitivity of tumors to drugs.

¹ This research was supported by IRG-58-34 from the American Cancer Society, a grant from the American Heart Association, Pennsylvania Affiliate (to D. G. H.), NIH National Research Service Award postdoctoral fellowship HL 08614 (to R. J. M.), and NIH Grant CA 43917 (to D. G. H. and J. S. L.).

² To whom requests for reprints should be addressed, at Department of Pharmacology, E1347 Biomedical Science Tower, University of Pittsburgh, Pittsburgh, PA 15261. Phone: (412) 383-7783; Fax: (412) 648-1945.

Received 7/ 8/96. Accepted 7/31/96.

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