Antiangiogenic therapy decreases integrin expression in normalized tumor blood vessels.
Tumor blood vessels normalized by antiangiogenic therapy may provide improved delivery of chemotherapeutic agents during a window of time but it is unknown how protein expression in tumor vascular endothelial cells changes. We evaluated the distribution of RGD-4C phage, which binds alpha(v)beta(3), alpha(v)beta(5), and alpha(5)beta(1) integrins on tumor blood vessels before and after antiangiogenic therapy. Unlike the control phage, fd-tet, RGD-4C phage homed to vascular endothelial cells in spontaneous tumors in RIP-Tag2 transgenic mice in a dose-dependent fashion. The distribution of phage was similar to alpha(v)beta(3) and alpha(5)beta(1) integrin expression. Blood vessels that survived treatment with AG-013736, a small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, had only 4% as much binding of RGD-4C phage compared with vessels in untreated tumors. Cellular distribution of RGD-4C phage in surviving tumor vessels matched the alpha(5)beta(1) integrin expression. The reduction in integrin expression on tumor vessels after antiangiogenic therapy raises the possibility that integrin-targeted delivery of diagnostics or therapeutics may be compromised. Efficacious delivery of drugs may benefit from identification by in vivo phage display of targeting peptides that bind to tumor blood vessels normalized by antiangiogenic agents.
Yao
Virginia J
VJ
Department of Anatomy, University of California, San Francisco, California 91413-0452, USA.
Ozawa
Michael G
MG
Varner
Amanda S
AS
Kasman
Ian M
IM
Chanthery
Yvan H
YH
Pasqualini
Renata
R
Arap
Wadih
W
McDonald
Donald M
DM
D007516:Adenoma, Islet Cell / Q000098:blood supply* / Q000628:therapy; D000818:Animals; D000077784:Axitinib; D017104:Bacteriophage M13 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D009842:Oligopeptides / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000628:therapy; D013379:Substrate Specificity
D007093:Imidazoles; D007191:Indazoles; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D000077784:Axitinib