Systemic gene delivery expands the repertoire of effective antiangiogenic agents

Cationic liposome-DNA complex (CLDC)-based intravenous gene delivery target s gene expression to vascular endothelial cells, macrophages and tumor cell s. We used systemic gene delivery to identify anti-angiogenic gene products effective against metastatic spread in tumor-bearing mice, Specifically, C LDC-based intravenous delivery of the p53 and GM-CSF genes were each as eff ective as the potent antiangiogenic gene, angiostatin, in reducing both tum or metastasis and tumor angiogenesis, Combined delivery of these genes did not increase anti-tumor activity, further suggesting that each gene appeare d to produce its antimetastatic activity through a common antiangiogenic pa thway. CLDC-based intravenous delivery of the human wild type p53 gene tran sfected up to 80% of tumor cells metastatic to lung. Furthermore, it specif ically induced the expression of the potent antiangiogenic gene, thrombospo ndin-l, indicating that p53 gene delivery in vivo may inhibit angiogenesis by inducing endogenous thrombospondin-l expression. CLDC-based delivery als o identified a novel antitumor activity for the metastasis suppressor gene CC3, Thus, CLDC-based intravenous gene delivery can produce systemic antian giogenic gene therapy using a variety of different genes and may be used to assess potential synergy of combined anti-tumor gene delivery and to ident ify novel activities for existing anti-tumor genes.