Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo

Sundaram Ramakrishnan, T. A. Olson, V. L. Bautch, D. Mohanraj

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. An endothelial cell-specific cytotoxic conjugate was prepared by chemically linking recombinant vascular endothelial growth factor (VEGF165) and a truncated diphtheria toxin molecule (DT385). The treatment of subconfluent cultures of human umbilical vein endothelial cells and human microvascular endothelial cells with the VEGF165-DT385 conjugate resulted in a selective, dose-dependent inhibition of growth. Parallel experiments with either the free toxin or a mixture of VEGF and the toxin polypeptide did not affect proliferation (DNA synthesis) of these cells. The selective cytotoxicity correlated with the appropriate receptor expression (KDR/flk-1 positive) on the target cells. VEGF-toxin conjugate inhibited the growth of a murine hemangioma-derived endothelial cell line (Py-4-1), which was positive for flk-1 expression. Under similar conditions, the conjugate did not affect the proliferation of a receptor-negative ovarian cancer cell line in vitro. In an in vivo model of angiogenesis, the VEGF165-DT385 conjugate blocked basic fibroblast growth factor-induced neovascularization of the chick chorioallantoic membrane. These studies demonstrate the successful targeting of a cytotoxic polypeptide to proliferating vascular endothelial cells (normal and tumorigenic) and the potential utility of such conjugates in blocking tumor neovascularization.

Original languageEnglish (US)
Pages (from-to)1324-1330
Number of pages7
JournalCancer Research
Volume56
Issue number6
StatePublished - Mar 15 1996
Externally publishedYes

Fingerprint

Immunotoxins
Vascular Endothelial Growth Factor A
Endothelial Cells
Cell Proliferation
Growth
Diphtheria Toxin
Chorioallantoic Membrane
Cell Line
Neoplasms
Peptides
Human Umbilical Vein Endothelial Cells
Fibroblast Growth Factor 2
Hemangioma
Ovarian Neoplasms
In Vitro Techniques
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo. / Ramakrishnan, Sundaram; Olson, T. A.; Bautch, V. L.; Mohanraj, D.

In: Cancer Research, Vol. 56, No. 6, 15.03.1996, p. 1324-1330.

Research output: Contribution to journalArticle

@article{a2503c0d9be9454c96c936ddc4e4c527,
title = "Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo",
abstract = "Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. An endothelial cell-specific cytotoxic conjugate was prepared by chemically linking recombinant vascular endothelial growth factor (VEGF165) and a truncated diphtheria toxin molecule (DT385). The treatment of subconfluent cultures of human umbilical vein endothelial cells and human microvascular endothelial cells with the VEGF165-DT385 conjugate resulted in a selective, dose-dependent inhibition of growth. Parallel experiments with either the free toxin or a mixture of VEGF and the toxin polypeptide did not affect proliferation (DNA synthesis) of these cells. The selective cytotoxicity correlated with the appropriate receptor expression (KDR/flk-1 positive) on the target cells. VEGF-toxin conjugate inhibited the growth of a murine hemangioma-derived endothelial cell line (Py-4-1), which was positive for flk-1 expression. Under similar conditions, the conjugate did not affect the proliferation of a receptor-negative ovarian cancer cell line in vitro. In an in vivo model of angiogenesis, the VEGF165-DT385 conjugate blocked basic fibroblast growth factor-induced neovascularization of the chick chorioallantoic membrane. These studies demonstrate the successful targeting of a cytotoxic polypeptide to proliferating vascular endothelial cells (normal and tumorigenic) and the potential utility of such conjugates in blocking tumor neovascularization.",
author = "Sundaram Ramakrishnan and Olson, {T. A.} and Bautch, {V. L.} and D. Mohanraj",
year = "1996",
month = "3",
day = "15",
language = "English (US)",
volume = "56",
pages = "1324--1330",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo

AU - Ramakrishnan, Sundaram

AU - Olson, T. A.

AU - Bautch, V. L.

AU - Mohanraj, D.

PY - 1996/3/15

Y1 - 1996/3/15

N2 - Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. An endothelial cell-specific cytotoxic conjugate was prepared by chemically linking recombinant vascular endothelial growth factor (VEGF165) and a truncated diphtheria toxin molecule (DT385). The treatment of subconfluent cultures of human umbilical vein endothelial cells and human microvascular endothelial cells with the VEGF165-DT385 conjugate resulted in a selective, dose-dependent inhibition of growth. Parallel experiments with either the free toxin or a mixture of VEGF and the toxin polypeptide did not affect proliferation (DNA synthesis) of these cells. The selective cytotoxicity correlated with the appropriate receptor expression (KDR/flk-1 positive) on the target cells. VEGF-toxin conjugate inhibited the growth of a murine hemangioma-derived endothelial cell line (Py-4-1), which was positive for flk-1 expression. Under similar conditions, the conjugate did not affect the proliferation of a receptor-negative ovarian cancer cell line in vitro. In an in vivo model of angiogenesis, the VEGF165-DT385 conjugate blocked basic fibroblast growth factor-induced neovascularization of the chick chorioallantoic membrane. These studies demonstrate the successful targeting of a cytotoxic polypeptide to proliferating vascular endothelial cells (normal and tumorigenic) and the potential utility of such conjugates in blocking tumor neovascularization.

AB - Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. An endothelial cell-specific cytotoxic conjugate was prepared by chemically linking recombinant vascular endothelial growth factor (VEGF165) and a truncated diphtheria toxin molecule (DT385). The treatment of subconfluent cultures of human umbilical vein endothelial cells and human microvascular endothelial cells with the VEGF165-DT385 conjugate resulted in a selective, dose-dependent inhibition of growth. Parallel experiments with either the free toxin or a mixture of VEGF and the toxin polypeptide did not affect proliferation (DNA synthesis) of these cells. The selective cytotoxicity correlated with the appropriate receptor expression (KDR/flk-1 positive) on the target cells. VEGF-toxin conjugate inhibited the growth of a murine hemangioma-derived endothelial cell line (Py-4-1), which was positive for flk-1 expression. Under similar conditions, the conjugate did not affect the proliferation of a receptor-negative ovarian cancer cell line in vitro. In an in vivo model of angiogenesis, the VEGF165-DT385 conjugate blocked basic fibroblast growth factor-induced neovascularization of the chick chorioallantoic membrane. These studies demonstrate the successful targeting of a cytotoxic polypeptide to proliferating vascular endothelial cells (normal and tumorigenic) and the potential utility of such conjugates in blocking tumor neovascularization.

UR - http://www.scopus.com/inward/record.url?scp=0029915612&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029915612&partnerID=8YFLogxK

M3 - Article

C2 - 8640821

AN - SCOPUS:0029915612

VL - 56

SP - 1324

EP - 1330

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 6

ER -