Monitoring hypoxia and vasculature during bevacizumab treatment in a murine colorectal cancer model.
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.
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
L
L
Heijmen
E G W
EG
Ter Voert
C J A
CJ
Punt
A
A
Heerschap
W J G
WJ
Oyen
J
J
Bussink
C G J
CG
Sweep
P
P
Laverman
P N
PN
Span
L F
LF
de Geus-Oei
O C
OC
Boerman
H W M
HW
van Laarhoven
D020533:Angiogenesis Inhibitors / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000494:pharmacology*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019788:Fluorodeoxyglucose F18; D000860:Hypoxia / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D009593:Nitroimidazoles; D049268:Positron-Emission Tomography; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; D000068258:Bevacizumab; C033815:pimonidazole; D008920:Misonidazole
bevacizumab; colorectal cancer; hypoxia; mechanism of resistance; tumor vasculature and microenvironment