Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest.
The antitumoral effects that follow the local delivery of the N-terminal fragment of human plasminogen (angiostatin K3) have been studied in two xenograft murine models. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule from the cytomegalovirus promoter (AdK3). In in vitro studies, AdK3 selectively inhibited endothelial cell proliferation and disrupted the G2/M transition induced by M-phase-promoting factors. AdK3-infected endothelial cells showed a marked mitosis arrest that correlated with the down-regulation of the M-phase phosphoproteins. A single intratumoral injection of AdK3 into preestablished rat C6 glioma or human MDA-MB-231 breast carcinoma grown in athymic mice was followed by a significant arrest of tumor growth, which was associated with a suppression of neovascularization within and at the vicinity of the tumors. AdK3 therapy also induced a 10-fold increase in apoptotic tumor cells as compared with a control adenovirus. Furthermore, we showed that systemic injection of AdK3 delayed C6 tumor establishment and growth, confirming that angiostatin can function in a paracrin manner. Our data support the concept that targeted antiangiogenesis, using adenovirus-mediated gene transfer, represents a promising alternative strategy for delivering antiangiogenic factors as their bolus injections present unsolved pharmacological problems.
Griscelli
F
F
le Centre National de la Recherche Scientifique Unite de Recherche Associée 1301/Rhône-Poulenc Rorer Gencell, Institut Gustave Roussy, 94805 Villejuif, France. grisceli@igr.fr
Li
H
H
Bennaceur-Griscelli
A
A
Soria
J
J
Opolon
P
P
Soria
C
C
Perricaudet
M
M
Yeh
P
P
Lu
H
H
D000256:Adenoviridae; D043168:Angiostatins; D000818:Animals; D002455:Cell Division / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000235:genetics; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics*; D010958:Plasminogen / Q000235:genetics*; D051381:Rats
D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen