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

AIMS:

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.

INNOVATION:

Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques.

CONCLUSION:

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: Shingo Matsumoto, Keita Saito, Yoichi Takakusagi, Masayuki Matsuo, Jeeva P Munasinghe, Herman D Morris, Martin J Lizak, Hellmut Merkle, Keiji Yasukawa, Nallathamby Devasahayam, Sankaran Suburamanian, James B Mitchell, Murali C Krishna
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 21 Issue 8 Pg. 1145-55 (Sep 10 2014) ISSN: 1557-7716 [Electronic] United States
• PMID: 24597714 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Contrast Media
• Cyclic N-Oxides
• Indoles
• Pyrroles
• Pyruvic Acid
• Oxygen
• Sunitinib

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Cell Line, Tumor
• Contrast Media (metabolism)
• Cyclic N-Oxides (metabolism)
• Electron Spin Resonance Spectroscopy
• Female
• Humans
• Indoles (pharmacology, therapeutic use)
• Magnetic Resonance Imaging
• Mice, Inbred C3H
• Mice, Nude
• Neoplasms (blood supply, drug therapy, metabolism)
• Neovascularization, Pathologic (metabolism, pathology, prevention & control)
• Oxidation-Reduction
• Oxygen (metabolism)
• Pyrroles (pharmacology, therapeutic use)
• Pyruvic Acid (metabolism)
• Sunitinib
• Xenograft Model Antitumor Assays