Dienst_VCAM-1.docVIP

Dienst_VCAM-1 ----------------------- 页面 1----------------------- ARTICLEARTICLES Specifi c Occlusion of Murine and Human Tumor Vasculature by VCAM-1 – Targeted Recombinant Fusion Proteins Ariane Dienst, Andrea Grunow, Maike Unruh, Berit Rabausch, Jacques E. Nor, Jochen W. U. Fries, Claudia Gottstein ( 8–10 ). Damage to endothelial cells results in the induction of Background: The tumor vasculature is increasingly recognized the coagulation cascade, causing intratumoral vessel occlusion as a target for cancer therapy. We developed and evaluated and subsequent tumor necrosis ( 11 ). In clinical studies, vascular recombinant fusion proteins targeting the coagulation-inducing occluding agents have antitumor effects in locoregional settings. protein soluble tissue factor (sTF) to the luminal tumor endo- For example, tumor necrosis factor α(TNF-α ) – based isolated thelial antigen vascular cell adhesion molecule 1 (VCAM-1, limb perfusions of localized soft tissue sarcomas or melanomas CD106). Methods: We generated fusion proteins consisting of resulted in remission rates of 90% – 100% in some studies sTF fused to antibody fragments directed against mouse or [reviewed in Eggermont et al. ( 12 )]. The antitumor effect was human VCAM-1 and characterized them in vitro by fl ow caused by vascular occlusion and subsequent necrosis ( 13 , 14 ). cytometry, surface plasmon resonance, and two-stage coagu- Although this particular treatment was too toxic for systemic lation assays. Their therapeutic effects were tested in