Targeting the tumor vasculature: inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate

Int J Cancer. 1997 Dec 10;73(6):865-70. doi: 10.1002/(sici)1097-0215(19971210)73:6<865::aid-ijc17>;2-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diphtheria Toxin / chemistry
  • Diphtheria Toxin / therapeutic use*
  • Endothelial Growth Factors / chemistry
  • Endothelial Growth Factors / therapeutic use*
  • Female
  • Hemorrhage / chemically induced
  • Hemorrhage / pathology
  • Humans
  • Immunotoxins / chemistry
  • Immunotoxins / therapeutic use*
  • Kidney / blood supply
  • Kidney / drug effects
  • Liver / blood supply
  • Liver / drug effects
  • Lung / blood supply
  • Lung / drug effects
  • Lymphokines / chemistry
  • Lymphokines / therapeutic use*
  • Mice
  • Mice, Nude
  • Necrosis
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Ovarian Neoplasms / blood supply*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Diphtheria Toxin
  • Endothelial Growth Factors
  • Immunotoxins
  • Lymphokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors