Monitoring hypoxia and vasculature during bevacizumab treatment in a murine colorectal cancer model

• Published in: Contrast media and molecular imaging Vol. 9; no. 3; p. 237
• Main Authors: Heijmen, L, Ter Voert, E G W, Punt, C J A, Heerschap, A, Oyen, W J G, Bussink, J, Sweep, C G J, Laverman, P, Span, P N, de Geus-Oei, L F, Boerman, O C, van Laarhoven, H W M
• Format: Journal Article
• Language: English
• Published: England 01.05.2014
• Subjects: Angiogenesis Inhibitors - blood; Angiogenesis Inhibitors - pharmacology; Animals; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - pharmacology; Bevacizumab; Colorectal Neoplasms - blood supply; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Enzyme-Linked Immunosorbent Assay; Female; Fluorodeoxyglucose F18; Hypoxia - diagnosis; Hypoxia - drug therapy; Hypoxia - metabolism; Immunoenzyme Techniques; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Nude; Misonidazole - analogs & derivatives; Neovascularization, Pathologic - diagnosis; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Nitroimidazoles; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiopharmaceuticals; bevacizumab; hypoxia; mechanism of resistance; colorectal cancer; tumor vasculature and microenvironment
• ISSN: 1555-4317
• DOI: 10.1002/cmmi.1564

The purpose of this study was to assess the effect of bevacizumab on vasculature and hypoxia in a colorectal tumor model. Nude mice with subcutaneous LS174T tumors were treated with bevacizumab or saline. To assess tumor properties, separate groups of mice were imaged using (18) F-Fluoromisonidazole (FMISO) and (18) F-Fluorodeoxyglucose (FDG) positron emission tomography or magnetic resonance imaging before and 2, 6 and 10 days after the start of treatment. Tumors were harvested after imaging to determine hypoxia and vascular density immunohistochemically. The T2 * time increased significantly less in the bevacizumab group. FMISO uptake increased more over time in the control group. Vessel density significantly decreased in the bevacizumab-treated group. The Carbonic anhydrase 9 (CAIX) and glucose uptake transporter 1 (GLUT1) fractions were higher in bevacizumab-treated tumors. However, the hypoxic fraction showed no significant difference. Bevacizumab led to shorter T2 * times and higher GLUT1 and CAIX expression, suggesting an increase in hypoxia and a higher glycolytic rate. This could be a mechanism of resistance to bevacizumab. The increase in hypoxia, however, could not be demonstrated by pimonidazole/FMISO, possibly because distribution of these tracers is hampered by bevacizumab-induced effects on vascular permeability and perfusion.