REGIONAL SUPPRESSION OF TUMOR-GROWTH BY IN-VIVO TRANSFER OF A CDNA-ENCODING A SECRETED FORM OF THE EXTRACELLULAR DOMAIN OF THE FLT-1 VASCULAR ENDOTHELIAL GROWTH-FACTOR RECEPTOR

Vascular endothelial growth factor (VEGF), a potent angiogenic mediato r, is overexpressed in most solid tumors. On the basis of the knowledg e that solid tumor growth beyond a small volume is critically dependen t on angiogenesis, and that adenovirus (Ad) vectors can mediate effici ent in vivo gene transfer and expression, we hypothesized that Ad-medi ated transfer of a secreted form of the extracellular domain of the fl t-1 VEGF receptor (Adsflt) would suppress tumor growth on a regional b asis. To evaluate this concept, three tumor models were examined using a murine colon carcinoma cell line and syngeneic BALB/c mice. First, mice with preestablished splenic CT26.CL25 tumors and liver metastases were given Adsflt on AdNull intravenously and, after 15 days, spleens and livers were harvested to quantify tumor burden. Adslft-treated an imals had minimal residual splenic tumors and liver metastases; in con trast, control animals had bulky splenic tumors and extensive liver me tastases (p < 0.003). Second, mice with preestablished lung metastases showed a significant reduction in pulmonary metastases with regionall y administered Adslft (intratracheal, p < 0.02) but not when the vecto r was systemically administered (intravenous, p > 0.9). Finally, mice with primary subcutaneous tumors treated with intratumoral administrat ion of Adslft showed significant tumor suppression (p < 0.05) not obse rved in AdNull-treated mice or mice given Adslft intravenously (p > 0. 3). We conclude that Ad-mediated in vivo regional delivery of a secret ed form of the extracellular domain of the flt-1 VEGF receptor can eff ectively inhibit regional tumor growth, a strategy that may provide a means to control tumor growth within the treated organ without the ris k of systemic antiangiogenesis.