Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells.
Angiogenesis is a critical step in a benign tumor's evolution toward malignancy and metastasis. Tumor cells acquire such a phenotype by their ability to secrete angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF receptors (VEGFRs) flt-1/VEGFR-1 and Flk-1/ KDR/VEGFR-2 are restricted to activated endothelial cells, with the highest expression being in the tumor vasculature. The present study was undertaken to target the VEGFRs. Targeted toxins were developed by recombinant methods by fusing VEGF165 or VEGF121 to the diphtheria toxin (DT) translocation and enzymatic domain (DT390-VEGF165 or DT390-VEGF121). 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 tumor type that expresses high levels of VEGFRs. These fusion proteins completely inhibit the basic fibroblast growth factor-induced growth of new blood vessels in the chick chorioallantoic membrane assay. Furthermore, the fusion toxin substantially retards the growth of Kaposi's sarcoma tumors in mice. Because nearly all tumors induce local angiogenesis with high VEGFR expression, VEGF-derived toxins may have wide application in cancer therapy.
Arora
N
N
Centre for Biochemical Technology, Delhi, India.
Masood
R
R
Zheng
T
T
Cai
J
J
Smith
D L
DL
Gill
P S
PS
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004167:Diphtheria Toxin / Q000627:therapeutic use / Q000633:toxicity*; D016228:Endothelial Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D000922:Immunotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D008222:Lymphokines / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004167:Diphtheria Toxin; D016228:Endothelial Growth Factors; D000922:Immunotoxins; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors