Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia.
Because antiangiogenic therapies inhibit the growth of new tumor-associated blood vessels, as well as prune newly formed vasculature, they would be expected to reduce the supply of oxygen and thus increase tumor hypoxia. However, it is not clear if antiangiogenic treatments lead only to consistent and sustained increases in hypoxia, or transient decreases in tumor hypoxia along with periods of increased hypoxia. We undertook a detailed analysis of an orthotopically transplanted human breast carcinoma (MDA-MB-231) over a 3-week treatment period using DC101, an anti-vascular endothelial growth factor receptor 2 antibody. We observed consistent reductions in microvascular density, blood flow (measured by high-frequency micro-ultrasound), and perfusion. These effects resulted in an increase in the hypoxic tumor fraction, measured with an exogenous marker, pimonidazole, concurrent with an elevation in hypoxia-inducible factor-1alpha expression, an endogenous marker. The increase in tumor hypoxia was evident within 5 days and remained so throughout the entire course of treatment. Vascular perfusion and flow were impaired at days 2, 5, 7, 8, 14, and 21 after the first injection, but not at 4 hours. A modest increase in the vessel maturation index was detected after the 3-week treatment period, but this was not accompanied by an improvement in vascular function. These results suggest that sustained hypoxia and impairment of vascular function can be two consistent consequences of antiangiogenic drug treatment. The implications of the results are discussed, particularly with respect to how they relate to different theories for the counterintuitive chemosensitizing effects of antiangiogenic drugs, even when hypoxia is increased.
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Marcela
M
Franco
Shan
S
Man
Limor
L
Chen
Urban
U
Emmenegger
Yuval
Y
Shaked
Alison M
AM
Cheung
Allison S
AS
Brown
Daniel J
DJ
Hicklin
F Stuart
FS
Foster
Robert S
RS
Kerbel
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D040301:Vascular Endothelial Growth Factor Receptor-2