Systemic administration of a recombinant adenovirus encoding a HSA-Angiostatin kringle 1-3 conjugate inhibits MDA-MB-231 tumor growth and metastasis in a transgenic model of spontaneous eye cancer.
We previously reported that intratumoral injection of AdK3, a recombinant adenovirus encoding human angiostatin kringle (K) 1 to 3, inhibits tumor vascularization and tumor growth. To reduce the serum clearance of this factor, we constructed an adenovirus (AdK3-HSA) that carries a chimeric gene encoding a fusion protein between angiostatin K1-3 and human serum albumin (HSA). This conjugate inhibited endothelial cell proliferation as efficiently as K1-3. K3-HSA serum concentrations in immunodeficient mice systemically injected with AdK3-HSA were dramatically higher than in AdK3-injected mice. Furthermore, the growth of MDA-MB-231 tumors grafted into nude mice that had been injected intravenously with AdK3-HSA was inhibited by 79% (versus 17% with AdK3). In TRP-1/SV40 Tag transgenic mice, which spontaneously develop eye tumors with brain metastases, intravenous injections of AdK3-HSA in newborn mice blocked metastatic dissemination efficiently and significantly, and prolonged survival by 3 weeks. After 2 months, only 46% of AdK3-HSA-treated animals developed micrometastases, whereas 94% of the AdCO1-injected group displayed numerous macrometastases. Nevertheless, ocular tumor growth was not modified because of impaired diffusion of the conjugate in the eye compartment. Our results show that HSA genetic coupling is an efficient way to increase the pharmacokinetics of circulating angiogenic inhibitors and thus their antitumoral activity.
Bouquet
C
C
UMR 8121, Vectorologie et Transfert de Gènes, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France. bouquet@igr.fr
Frau
E
E
Opolon
P
P
Connault
E
E
Abitbol
M
M
Griscelli
F
F
Yeh
P
P
Perricaudet
M
M
D000256:Adenoviridae / Q000235:genetics*; D043168:Angiostatins; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D004727:Endothelium / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005134:Eye Neoplasms / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D018082:Kringles; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012709:Serum Albumin / Q000235:genetics*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D043168:Angiostatins; D010958:Plasminogen