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 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.
Kong
H L
HL
Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center, New York 10021, USA.
Hecht
D
D
Song
W
W
Kovesdi
I
I
Hackett
N R
NR
Yayon
A
A
Crystal
R G
RG
D000256:Adenoviridae; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D018076:DNA, Complementary / Q000008:administration & dosage; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000098:blood supply / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012878:Skin Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary / Q000628:therapy; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1
D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1