Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases.
Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro, as determined in endothelial cell proliferation assays, and in vivo, by suppression of angiogenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (P < 0.001 and P < 0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy as a component in cancer therapy.
Sauter
B V
BV
Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Martinet
O
O
Zhang
W J
WJ
Mandeli
J
J
Woo
S L
SL
D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics* / Q000633:toxicity*; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics* / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins
D000970:Antineoplastic Agents; D043169:Endostatins; D010446:Peptide Fragments; D016222:Fibroblast Growth Factor 2; D003094:Collagen