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

Timothy A. Olson, D. Mohanraj, Sabita Roy, S. Ramakrishnan

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)865-870
Number of pages6
JournalInternational Journal of Cancer
Volume73
Issue number6
DOIs
StatePublished - Dec 10 1997
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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