ANTIANGIOGENIC GENE-THERAPY TARGETING THE ENDOTHELIUM-SPECIFIC RECEPTOR TYROSINE KINASE TIE2

Angiogenesis is required for tumor growth and metastasis, and inhibiti on of angiogenesis is a promising approach for anticancer therapy, Tie 2 (a.k.a Tek) is an endothelium-specific receptor tyrosine kinase know n to play a role in tumor angiogenesis, To explore the therapeutic pot ential of blocking the Tie2 pathway, an adenoviral vector was construc ted to deliver a recombinant, soluble Tie2 receptor (AdExTek) capable of blocking Tie2 activation. Two days after i.v. injection of AdExTek, the plasma concentration of ExTek exceeded 1 mg/ml and was maintained for about 8 days. Administration of AdExTek to mice with two differen t well established primary tumors, a murine mammary carcinoma (4T1) or a murine melanoma (B16F10.9), significantly inhibited the growth rate of both tumors (64% and 47%, respectively), To study the effect of Ex Tek on tumor metastasis, both tumor cell lines were coinjected i.v. wi th either AdExTek or a control virus. Mice coinjected with control vir us developed numerous large, well vascularized lung metastases, In con trast, mice coinjected with AdExTek virus developed few, if any, gross ly apparent metastases, and histologic examination revealed only small avascular clusters of tumor cells, Administration of AdExTek also inh ibited tumor metastasis when delivered at the time of surgical excisio n of primary tumors in a clinically relevant model of tumor metastasis . This study demonstrates the potential utility of gene therapy for sy stemic delivery of an antiangiogenic agent targeting an endothelium-sp ecific receptor, Tie2.