Angiostatin gene transfer: Inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest

• DOI: 10.1073/pnas.95.11.6367
• Publication Date: 2002-07-26T14:40:11Z
• Authors: Frank Griscelli; Hong Li; Annelise Bennaceu...; Jeannette Soria; Paule Opolon; Claudine Soria; Michel Perricaudet; Patrice Yeh; He Lu
• Keywords: 0301 basic medicine; Neovascularization, Pathologic; Genetic Vectors; Gene Transfer Techniques; Mitosis; Plasminogen; Neoplasms, Experimental; Peptide Fragments; Adenoviridae; Rats; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Animals; Humans; Endothelium, Vascular; Angiostatins; Cell Division

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 G 2 /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.