title: In vivo imaging of tumor physiological, metabolic, and redox changes in response to the anti-angiogenic agent sunitinib: longitudinal assessment to identify transient vascular renormalization.
abstract: OBJECTIVE
  The tumor microenvironment is characterized by a highly reducing redox status, a low pH, and hypoxia. Anti-angiogenic therapies for solid tumors frequently function in two steps: the transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by the pruning of tumor blood vessels and the resultant cessation of nutrients and oxygen delivery required for tumor growth. Conventional anatomic or vascular imaging is impractical or insufficient to distinguish between the two steps of tumor response to anti-angiogenic therapies. Here, we investigated whether the noninvasive imaging of the tumor redox state and energy metabolism could be used to characterize anti-angiogenic drug-induced transient vascular normalization.
  
  
  RESULTS
  Daily treatment of squamous cell carcinoma (SCCVII) tumor-bearing mice with the multi-tyrosine kinase inhibitor sunitinib resulted in a rapid decrease in tumor microvessel density and the suppression of tumor growth. Tumor pO2 imaging by electron paramagnetic resonance imaging showed a transient increase in tumor oxygenation after 2-4 days of sunitinib treatment, implying improved tumor perfusion. During this window of vascular normalization, magnetic resonance imaging of the redox status using an exogenously administered nitroxide probe and hyperpolarized (13)C MRI of the metabolic flux of pyruvate/lactate couple revealed an oxidative shift in tumor redox status.
  
  
  METHODS
  Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques.
  
  
  CONCLUSIONS
  A multimodal imaging approach to characterize physiological, metabolic, and redox changes in tumors is useful to distinguish between the different stages of anti-angiogenic treatment.
authors.affiliation: 1 Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Keita
authors.initials: K
authors.lastname: Saito
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takakusagi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsuo
authors.forename: Jeeva P
authors.initials: JP
authors.lastname: Munasinghe
authors.forename: Herman D
authors.initials: HD
authors.lastname: Morris
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lizak
authors.forename: Hellmut
authors.initials: H
authors.lastname: Merkle
authors.forename: Keiji
authors.initials: K
authors.lastname: Yasukawa
authors.forename: Nallathamby
authors.initials: N
authors.lastname: Devasahayam
authors.forename: Sankaran
authors.initials: S
authors.lastname: Suburamanian
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D019289:Pyruvic Acid / Q000378:metabolism; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D003497:Cyclic N-Oxides; D007211:Indoles; D011758:Pyrroles; D019289:Pyruvic Acid; D010100:Oxygen; D000077210:Sunitinib