Gene transfer of the vascular endothelial growth factor receptor flt-1 suppresses pulmonary metastasis associated with lung growth.
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.
Mae
Masahiro
M
Department of Genetic Medicine, Weill Medical College of Cornell University, 515 East 71st Street, Suite 1000, New York, NY 10021, USA.
O'Connor
Timothy P
TP
Crystal
Ronald G
RG
D000230:Adenocarcinoma / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011013:Pneumonectomy; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D040281:Vascular Endothelial Growth Factor Receptor-1; D001616:beta-Galactosidase