Targeting the tumor vasculature: inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate.
Tumor-derived vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) plays an important role in neovascularization and the development of tumor stroma. Furthermore, VEGF receptors are over-expressed in the endothelial cells of tumor vasculature and almost non-detectable in the vascular endothelium of adjoining normal tissues. The differential expression of receptor offers a selective advantage for targeting cytotoxic toxin polypeptides. We have prepared a vascular targeting reagent by chemically linking recombinant VEGF to a truncated form of diphtheria toxin. The VEGF-toxin conjugate was selectively toxic to endothelial cell lines and inhibited experimental neovascularization of the chick chorioallantoic membrane. In the present study, we examined the effects of VEGF-toxin conjugate on solid tumor growth. Athymic nude mice with established subcutaneous tumors were treated with daily intraperitoneal injections of the VEGF-toxin conjugate or free toxin. When compared with control animals treated with the toxin polypeptide alone, the conjugate-treated animals displayed a significant inhibition of tumor growth. Histological analysis of tumors from conjugate-treated animals revealed hemorrhagic necrosis consistent with a vascular-mediated injury. In contrast, highly vascularized normal tissues from conjugate-treated animals demonstrated no evidence of hemorrhage or tissue injury. The conjugate was well tolerated without apparent toxicities. Our results illustrate the anti-tumor activity of a VEGF-toxin conjugate selectively targeting the tumor neovasculature.
Olson
T A
TA
Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Mohanraj
D
D
Roy
S
S
Ramakrishnan
S
S
D000818:Animals; D004167:Diphtheria Toxin / Q000737:chemistry / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008222:Lymphokines / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004167:Diphtheria Toxin; D016228:Endothelial Growth Factors; D000922:Immunotoxins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors