Adenovirus-mediated delivery of antiangiogenic genes as an antitumor approach.
Based on the observation that the growth of solid tumors is dependent on the formation of new blood vessels, therapeutic strategies aimed at inhibiting angiogenesis have been proposed. A number of proteins with angiostatic activity have been described, but their development as therapeutic agents has been hampered by difficulties in their production and their poor pharmacokinetics. These limitations may be resolved using a gene therapy approach whereby the genes are delivered and expressed in vivo. Here we compared adenoviral delivery of endostatin, proliferin-related protein (PRP), and interferon-inducible protein 10 (IP10) genes. Recombinant adenoviruses carrying the three angiostatic genes express biologically active gene products as determined in vitro in endothelial cell proliferation and migration assays, and in vivo by inhibition of neoangiogenesis in rat chambers. Eradication of established tumors in vivo, in the murine B16F10 melanoma model in immunocompetent mice, was not achieved by intratumoral injection of the different vectors. However, the combination of intravenous plus intratumoral injections allowed rejection of tumors. Ad-PRP or Ad-IP10 were significantly more efficient than Ad-endostatin, leading to complete tumor rejection and prolonged survival in a high proportion of treated animals. These data support the use of in vivo gene delivery approaches to produce high-circulating and local levels of antiangiogenic agents for the therapy of local and metastatic human tumors.
Régulier
E
E
TRANSGENE S.A., Strasbourg, France.
Paul
S
S
Marigliano
M
M
Kintz
J
J
Poitevin
Y
Y
Ledoux
C
C
Roecklin
D
D
Cauet
G
G
Calenda
V
V
Homann
H E
HE
D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000235:genetics; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000008:administration & dosage* / Q000235:genetics; D003094:Collagen / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D004338:Drug Combinations; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology; D005337:Fibrin / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000517:prevention & control; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000235:genetics; D011257:Pregnancy Proteins / Q000008:administration & dosage* / Q000235:genetics; D011509:Proteoglycans / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D001672:Biocompatible Materials; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004338:Drug Combinations; D043169:Endostatins; D007797:Laminin; D010446:Peptide Fragments; C057074:Plfr protein, mouse; D011257:Pregnancy Proteins; C489178:Prl7d1 protein, rat; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D005337:Fibrin; D003094:Collagen