Systemic gene delivery expands the repertoire of effective antiangiogenic agents.
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.
Liu
Y
Y
Geraldine Brush Cancer Research Institute at the California Pacific Medical Center, San Francisco, California 94115, USA.
Thor
A
A
Shtivelman
E
E
Cao
Y
Y
Tu
G
G
Heath
T D
TD
Debs
R J
RJ
D043168:Angiostatins; D000818:Animals; D015870:Gene Expression; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D010446:Peptide Fragments / Q000235:genetics; D010958:Plasminogen / Q000235:genetics; D019700:Thrombospondin 1 / Q000235:genetics
D010446:Peptide Fragments; D019700:Thrombospondin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D043168:Angiostatins; D010958:Plasminogen