1. Radiat Res. 2009 Nov;172(5):584-91.

Decrease in tumor cell oxygen consumption after treatment with vandetanib
(ZACTIMA; ZD6474) and its effect on response to radiotherapy.

Ansiaux R, Dewever J, Grégoire V, Feron O, Jordan BF, Gallez B.

Biomedical Magnetic Resonance Unit, Louvain Drug Research Institute, Université
Catholique de Louvain, B-1200 Brussels, Belgium.

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.

PMID: 19883226 [PubMed - in process]