Gene Transfer of the VEGF Receptor flt-1 Suppresses Pulmonary Metastasis Associated with Lung Growth

Key words: (1) compensatory lung growth; (2) pneumonectomy; (3) lung metastasis; (4) adenovirus-mediated gene therapy; and (5) anti-angiogenesis.Abstract Growth of solid tumor metastases is critically dependent on angiogenesis. We hypothesized that an " angiogenic-rich " milieu, as in pneumonectomy-induced lung growth, would be conducive to growth of pulmonary metastases, and that transfer of an anti-angiogenic gene would suppress tumor growth. Two weeks following left pneumonectomy in BALB/c mice, right lung mass increased 1.5-fold compared to controls (p<0.0001). Our pulmonary metastases model, intravenous administration of $-galactosidase ($gal)-marked CT26.CL25 colon carcinoma cells, resulted in diffuse metastases at 12 days post-administration. However, if left pneumonectomy was carried out 1 day before tumor cell administration, right lung mass was increased 1.7-fold after 12 days (p<0.001 compared to the right + left lung of controls), and $gal activity was greater (2.8-fold, p<0.05). To assess anti-angiogenesis therapy, tumor cells were administered 1 day after pneumonectomy and 1 day later, 5x10 8 pfu of Adsflt [an Ad vector expressing the extracellular portion of the flt-1 vascular endothelial growth factor (VEGF) receptor] was administered. Compared to controls, mice receiving Adsflt via intranasal or intravenous routes showed suppression of pneumonectomy-induced tumor growth (p<0.01, both routes compared to controls). Post-pneumonectomy lung growth enhances growth of lung metastases, but this can be suppressed with Adsflt anti-angiogenesis therapy.-3