Decrease in tumor cell oxygen consumption after treatment with vandetanib (ZACTIMA; ZD6474) and its effect on response to radiotherapy.
We investigated the early effects of vandetanib (ZACTIMA; ZD6474), an inhibitor of VEGFR-dependent angiogenesis, on tumor oxygenation and on the possible consequences of combining vandetanib with radiotherapy. Tumor oxygenation, perfusion, cellular consumption of oxygen, and radiation sensitivity were studied in transplantable liver tumors after daily doses of vandetanib (25 mg kg(-1) i.p.). Measurements of oxygenation (pO(2)) and tumor cell oxygen consumption were carried out using electron paramagnetic resonance (EPR), and perfusion parameters were assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Regrowth delay assays were performed after treatment with vandetanib alone, radiation alone or a combination of both treatments. Vandetanib induced an early increase in tumor oxygenation that did not correlate with remodeling of the tumor vasculature or with changes in tumor perfusion. A decrease in tumor cell oxygen consumption was observed that could have been responsible for this increase in tumor oxygenation. Consistent with this increase in tumor oxygenation, we found that vandetanib potentiated the tumor response to radiotherapy. Our results confirm that treatment with an inhibitor of VEGFR signaling reduces oxygen consumption rate by tumor cells. The observation that vandetanib causes an early increase in tumor oxygenation has implications for the timing and sequencing of treatment with VEGF signaling inhibitors in combination with radiation.
Ansiaux
Réginald
R
Biomedical Magnetic Resonance Unit, Louvain Drug Research Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Dewever
Julie
J
Grégoire
Vincent
V
Feron
Olivier
O
Jordan
Bénédicte F
BF
Gallez
Bernard
B
D000818:Animals; D003287:Contrast Media; D004578:Electron Spin Resonance Spectroscopy; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010101:Oxygen Consumption; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
D003287:Contrast Media; D010880:Piperidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib