Systemic gene delivery expands the repertoire of effective antiangiogenic agents

J Biol Chem. 1999 May 7;274(19):13338-44. doi: 10.1074/jbc.274.19.13338.

Abstract

Cationic liposome-DNA complex (CLDC)-based intravenous gene delivery targets gene expression to vascular endothelial cells, macrophages and tumor cells. We used systemic gene delivery to identify anti-angiogenic gene products effective against metastatic spread in tumor-bearing mice. Specifically, CLDC-based intravenous delivery of the p53 and GM-CSF genes were each as effective as the potent antiangiogenic gene, angiostatin, in reducing both tumor metastasis and tumor angiogenesis. Combined delivery of these genes did not increase anti-tumor activity, further suggesting that each gene appeared to produce its antimetastatic activity through a common antiangiogenic pathway. CLDC-based intravenous delivery of the human wild type p53 gene transfected up to 80% of tumor cells metastatic to lung. Furthermore, it specifically induced the expression of the potent antiangiogenic gene, thrombospondin-1, indicating that p53 gene delivery in vivo may inhibit angiogenesis by inducing endogenous thrombospondin-1 expression. CLDC-based delivery also identified a novel anti-tumor activity for the metastasis suppressor gene CC3. Thus, CLDC-based intravenous gene delivery can produce systemic antiangiogenic gene therapy using a variety of different genes and may be used to assess potential synergy of combined anti-tumor gene delivery and to identify novel activities for existing anti-tumor genes.

Publication types

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

MeSH terms

  • Angiostatins
  • Animals
  • Gene Expression
  • Gene Transfer Techniques*
  • Genes, p53 / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Humans
  • Melanoma, Experimental / blood supply*
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology
  • Mice
  • Neoplasm Metastasis / therapy*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / therapy*
  • Peptide Fragments / genetics
  • Plasminogen / genetics
  • Thrombospondin 1 / genetics

Substances

  • Peptide Fragments
  • Thrombospondin 1
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Angiostatins
  • Plasminogen