A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer.
Different antiangiogenic and antimetastatic recombinant adenoviruses were tested in a transgenic mouse model of metastatic ocular cancer (TRP1/SV40 Tag transgenic mice), which is a highly aggressive tumor, developed from the pigmented epithelium of the retina. These vectors, encoding amino-terminal fragments of urokinase plasminogen activator (ATF), angiostatin Kringles (K1-3), endostatin (ES) and canstatin (Can) coupled to human serum albumin (HSA) were injected to assess their metastatic and antiangiogenic activities in our model. Compared to AdCO1 control group, AdATF-HSA did not significantly reduce metastatic growth. In contrast, mice treated with AdK1-3-HSA, AdES-HSA and AdCan-HSA displayed significantly smaller metastases (1.19+/-1.19, 0.87+/-1.5, 0.43+/-0.56 vs controls 4.04+/-5.12 mm3). Moreover, a stronger inhibition of metastatic growth was obtained with AdCan-HSA than with AdK1-3-HSA (P=0.04). Median survival was improved by 4 weeks. A close correlation was observed between the effects of these viruses on metastatic growth and their capacity to inhibit tumor angiogenesis. Our study indicates that systemic antiangiogenic factors production by recombinant adenoviruses, particularly Can, might represent an effective way of delaying metastatic growth via inhibition of angiogenesis.
Frau
E
E
CNRS UMR 8121 Univ Paris Sud, Vectorologie et Transfert de Gènes, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.
Magnon
C
C
Opolon
P
P
Connault
E
E
Opolon
D
D
Beermann
F
F
Beerman
F
F
Abitbol
M
M
Perricaudet
M
M
Bouquet
C
C
D051696:Activating Transcription Factors / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000627:therapeutic use; D043168:Angiostatins / Q000235:genetics; D000818:Animals; D001798:Blood Proteins / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D024141:Collagen Type IV / Q000235:genetics; D043169:Endostatins / Q000235:genetics; D005134:Eye Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000235:genetics; D012709:Serum Albumin / Q000235:genetics*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D051696:Activating Transcription Factors; D020533:Angiogenesis Inhibitors; D001798:Blood Proteins; C502624:Col4a2 protein, mouse; D024141:Collagen Type IV; D043169:Endostatins; D010446:Peptide Fragments; D012709:Serum Albumin; D043168:Angiostatins; D014568:Urokinase-Type Plasminogen Activator