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 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 alpha 5, beta 1, or beta 3 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.
Hoyt
D G
DG
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Rusnak
J M
JM
Mannix
R J
RJ
Modzelewski
R A
RA
Johnson
C S
CS
Lazo
J S
JS
D000818:Animals; D000906:Antibodies; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology; D001485:Basement Membrane / Q000502:physiology; D002448:Cell Adhesion; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D005047:Etoposide / Q000633:toxicity*; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005353:Fibronectins; D005354:Fibrosarcoma / Q000098:blood supply*; D005780:Gelatin; D039482:Integrin alpha5; D019012:Integrin beta1 / Q000276:immunology / Q000502:physiology; D039661:Integrin beta3; D016023:Integrins / Q000502:physiology*; D007797:Laminin; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000502:physiology
D000906:Antibodies; D015703:Antigens, CD; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039482:Integrin alpha5; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; D007797:Laminin; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; C101396:glycyl-arginyl-alanyl-aspartyl-seryl-proline; D005047:Etoposide; D005780:Gelatin; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline