Regional Suppression of Tumor Growth by <i>In Vivo</i> Transfer of a cDNA Encoding a Secreted Form of the Extracellular Domain of the <i>flt-1</i> Vascular Endothelial Growth Factor Receptor

Abstract

Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, is overexpressed in most solid tumors. On the basis of the knowledge that solid tumor growth beyond a small volume is critically dependent on angiogenesis, and that adenovirus (Ad) vectors can mediate efficient in vivo gene transfer and expression, we hypothesized that Ad-mediated transfer of a secreted form of the extracellular domain of the flt-1 VEGF receptor (Adsflt) would suppress tumor growth on a regional basis. 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 animals had minimal residual splenic tumors and liver metastases; in contrast, control animals had bulky splenic tumors and extensive liver metastases (p < 0.003). Second, mice with preestablished lung metastases showed a significant reduction in pulmonary metastases with regionally administered Adslft (intratracheal, p < 0.02) but not when the vector was systemically administered (intravenous, p > 0.9). Finally, mice with primary subcutaneous tumors treated with intratumoral administration of Adslft showed significant tumor suppression (p < 0.05) not observed in AdNull-treated mice or mice given Adslft intravenously (p > 0.3). We conclude that Ad-mediated in vivo regional delivery of a secreted form of the extracellular domain of the flt-1 VEGF receptor can effectively inhibit regional tumor growth, a strategy that may provide a means to control tumor growth within the treated organ without the risk of systemic antiangiogenesis. It has been known that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of cancer by inducing angiogenesis. The present study is designed to evaluate the hypothesis that regional anti-VEGF therapy, and hence regional control of tumor growth, can be achieved by adenovirus (Ad)-mediated regional transfer of the cDNA that encodes a secreted form of the extracellular domain of the human flt-1 VEGF receptor (Adsflt). Using subcutaneous, liver metastatic, and lung metastatic models of tumor growth, the data demonstrate that the regional delivery of the sflt cDNA via an Ad vector dramatically inhibits the growth of preestablished tumors in animal models, but only within the organs to which the vector is administered, i.e., the Adsflt vector functions in a regional fashion.