Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells.
The vasculature of mouse breast tumor spheroids grown on mammary fat pad tissue in an intravital microscopy (IVM) viewing chamber was shown to derive from infiltrating angiogenic mammary vessels. The receptors tissue factor (TF), alpha V beta 3 integrin and Tie-2 were expressed on the vascular endothelium in the periphery but not in the center of the tumor spheroids nor in the mammary tissue nor in smooth muscle tissue, whereas Tie-1 and PCAM-1 were expressed extensively in the entire tumor and in the vascular endothelium of the entire tumor nodule and in normal mammary tissue. TF is a specific target for adenoviral vector-mediated cancer immunotherapy. Subcutaneous injection of the AdfVII/IgG(1)Fc vector leads to the release into the system circulation of a fVII/IgG(1)Fc immunoconjugate molecule that binds specifically and tightly to TF on vascular endothelial cells and tumor cells, activating a cytolytic immune response against the targeted cells. We show that a single administration of the AdfVII/IgG(1)Fc vector destroys the peripheral but not the central vasculature of a tumor spheroid, causing partial tumor regression; additional administrations prevent regeneration of the peripheral vasculature and regrowth of the tumor. These findings indicate that a critical parameter for optimizing tumor damage is the schedule for successive administrations of the AdfVII/IgG(1)Fc, which should coincide with the regeneration of the peripheral vasculature and continue until the tumor is destroyed.
Tang
Y
Y
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
Borgstrom
P
P
Maynard
J
J
Koziol
J
J
Hu
Z
Z
Garen
A
A
Deisseroth
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply / Q000737:chemistry / Q000628:therapy*; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000032:analysis / Q000378:metabolism; D018874:Spheroids, Cellular / Q000737:chemistry / Q000378:metabolism; D013925:Thromboplastin / Q000032:analysis / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D018796:Immunoconjugates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013925:Thromboplastin; D042810:Receptor, TIE-1