Vascular endothelial growth factor chimeric toxin is highly active againstendothelial cells

Angiogenesis is a critical step in a benign tumor's evolution toward malign ancy and metastasis. Tumor cells acquire such a phenotype by their ability to secrete angiogenic factors such as vascular endothelial growth factor (V EGF), VEGF receptors (VEGFRs) flt-1/VEGFR-1 and Flk-1/KDR/VEGFR-2 are restr icted to activated endothelial cells, with the highest expression being in the tumor vasculature. The present study was undertaken to target the VEGFR s, Targeted toxins were developed by recombinant methods by fusing VEGF,,, or VEGF,,, to the diphtheria toxin (DT) translocation and enzymatic domain (DT390-VEGF(165) or DT390-VEGF(121)). Both fusion proteins were found to be highly toxic to proliferating endothelial cells but not to vascular smooth muscle cells. The fusion protein is also active in Kaposi's sarcoma, a tum or type that expresses high levels of VEGFRs. These fusion proteins complet ely inhibit the basic fibroblast growth factor-induced growth of new blood vessels in the chick chorioallantoic membrane assay. Furthermore, the fusio n toxin substantially retards the growth of Kaposi's sarcoma tumors in mice . Because nearly all tumors induce local angiogenesis with high VEGFR expre ssion, VEGF-derived toxins may have wide application in cancer therapy.