Efficient infection of tumor endothelial cells by a capsid-modified adenovirus.
Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/35 may be useful in anticancer strategies targeting tumor endothelial cells.
Shinozaki
K
K
Carl C. Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Suominen
E
E
Carrick
F
F
Sauter
B
B
Kähäri
V-M
VM
Lieber
A
A
Woo
S L C
SL
Savontaus
M
M
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D036022:Capsid Proteins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000628:therapy; D042783:Endothelial Cells / Q000821:virology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000628:therapy; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000628:therapy* / Q000821:virology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D051381:Rats; D014161:Transduction, Genetic / Q000379:methods*; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
D015415:Biomarkers; D036022:Capsid Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2