title: Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia.
abstract: Structural and functional abnormalities in tumor blood vessels impact the delivery of oxygen and nutrients to solid tumors, resulting in chronic and cycling hypoxia. Although chronically hypoxic regions exhibit treatment resistance, more recently it has been shown that cycling hypoxic regions acquire prosurvival pathways. Angiogenesis inhibitors have been shown to transiently normalize the tumor vasculatures and enhance tumor response to treatments. However, the effect of antiangiogenic therapy on cycling tumor hypoxia remains unknown. Using electron paramagnetic resonance imaging and MRI in tumor-bearing mice, we have examined the vascular renormalization process by longitudinally mapping tumor partial pressure of oxygen (pO(2)) and microvessel density during treatments with a multi-tyrosine kinase inhibitor sunitinib. Transient improvement in tumor oxygenation was visualized by electron paramagnetic resonance imaging 2 to 4 days following antiangiogenic treatments, accompanied by a 45% decrease in microvessel density. Radiation treatment during this time period of improved oxygenation by antiangiogenic therapy resulted in a synergistic delay in tumor growth. In addition, dynamic oxygen imaging obtained every 3 minutes was conducted to distinguish tumor regions with chronic and cycling hypoxia. Sunitinib treatment suppressed the extent of temporal fluctuations in tumor pO(2) during the vascular normalization window, resulting in the decrease of cycling tumor hypoxia. Overall, the findings suggest that longitudinal and noninvasive monitoring of tumor pO(2) makes it possible to identify a window of vascular renormalization to maximize the effects of combination therapy with antiangiogenic drugs.
authors: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Shingo
authors: S
authors: Matsumoto
authors: Sonny
authors: S
authors: Batra
authors: Keita
authors: K
authors: Saito
authors: Hironobu
authors: H
authors: Yasui
authors: Rajani
authors: R
authors: Choudhuri
authors: Chandramouli
authors: C
authors: Gadisetti
authors: Sankaran
authors: S
authors: Subramanian
authors: Nallathamby
authors: N
authors: Devasahayam
authors: Jeeva P
authors: JP
authors: Munasinghe
authors: James B
authors: JB
authors: Mitchell
authors: Murali C
authors: MC
authors: Krishna
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply*; D015687:Cell Hypoxia / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D007211:Indoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010100:Oxygen / Q000378:metabolism*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D010100:Oxygen; D000077210:Sunitinib