Cediranib is a small-molecule pan-
vascular endothelial growth factor receptor inhibitor. The
tumor response to short-term
cediranib treatment was studied using dynamic contrast-enhanced and diffusion-weighted MRI at 7 T, as well as (18) F-
fluoromisonidazole positron emission tomography and histological markers. Rats bearing subcutaneous HT29 human
colorectal tumors were imaged at baseline; they then received three doses of
cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow-up imaging performed 2 h after the final
cediranib or vehicle dose.
Tumors were excised and evaluated for the perfusion marker
Hoechst 33342, the endothelial cell marker CD31, smooth muscle actin, intercapillary distance and
tumor necrosis. Dynamic contrast-enhanced MRI-derived parameters decreased significantly in
cediranib-treated
tumors relative to pretreatment values [the muscle-normalized initial area under the
gadolinium concentration curve decreased by 48% (p=0.002), the enhancing fraction by 43% (p=0.003) and K(trans) by 57% (p=0.003)], but remained unchanged in controls. No change between the pre- and post-treatment
tumor apparent diffusion coefficients in either the
cediranib- or vehicle-treated group was observed over the course of this study. The (18) F-
fluoromisonidazole mean standardized uptake value decreased by 33% (p=0.008) in the
cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31-positive vessels (59 per mm(2) ), the fraction of smooth muscle actin-positive vessels (80-87%) and the intercapillary distance (0.17 mm) were similar in
cediranib- and vehicle-treated groups. The fraction of perfused blood vessels in
cediranib-treated
tumors (81 ± 7%) was lower than that in vehicle controls (91 ± 3%, p=0.02). The necrotic fraction was slightly higher in
cediranib-treated rats (34 ± 12%) than in controls (26 ± 10%, p=0.23). These findings suggest that short-term treatment with
cediranib causes a decrease in
tumor perfusion/permeability across the
tumor cross-section, but changes in vascular morphology, vessel density or
tumor cellularity are not manifested at this early time point.