Gene Transfer of the Vascular Endothelial Growth Factor Receptor flt-1 Suppresses Pulmonary Metastasis Associated with Lung Growth

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 antiangiogenic gene would suppress tumor growth. Two weeks after left pneumonectomy in BALB/c mice, right lung mass increased 1.5-fold compared with controls (P < 0.0001). Our pulmonary metastases model, intravenous administration of beta-galactosidase (betagal)-marked CT26.CL25 colon carcinoma cells, resulted in diffuse metastases at 12 d after administration. However, if left pneumonectomy was performed 1 d before tumor cell administration, right lung mass was increased 1.7-fold after 12 d (P < 0.001 compared with the right + left lung of controls), and betagal activity was greater (2.8-fold, P < 0.05). To assess antiangiogenesis therapy, tumor cells were administered 1 d after pneumonectomy and 1 d later, 5 x 10(8) plaque-forming units of Adsflt (an Ad vector expressing the extracellular portion of the flt-1 vascular endothelial growth factor [VEGF] receptor) was administered. Compared with controls, mice receiving Adsflt via intranasal or intravenous routes showed suppression of pneumonectomy-induced tumor growth (P < 0.01, both routes compared with controls). Postpneumonectomy lung growth enhances growth of lung metastases, but this can be suppressed with Adsflt antiangiogenesis therapy.

Dynamic determination of oxygenation and lung compliance in murine pneumonectomy

“…Pulmonary surgical procedures in mice have been applied to a wide range of investigations including studies of gene expression (12), tumor biology (4) and lung regeneration (13). The economic benefits of Mus musculus , including its small size and short reproductive cycle, complement the experimental advantages of widely available and well-characterized inbred mouse strains (17).…”

Molecular diagnosis in lung diseases

“…In the last decade humanized antibodies, such as those against VEGF (Bevacizumab), have been developed to interfere with the neoangiogenesis © 1996-2015 in primary as well as metastatic carcinomas (89,90). However, anti-angiogenetic drugs can cause severe bleeding, especially in patients with centrally located squamous cell carcinomas.…”

Anti-angiogenic gene therapy of cancer: Current status and future prospects

“…In a study of Mae et al (2005), the effectiveness of an anti-angiogenesis as postsurgical treatment in suppression of growth and dissemination of lung metastasis following pneumonectomy was shown. In fact unilateral pneumonectomy initiates a rapid and diffusive hyperplasia of the remaining lung cells.…”