Response of HT29 colorectal xenograft model to cediranib assessed with super(18)F-fluoromisonidazole positron emission tomography, dynamic contrast-enhanced and diffusion-weighted MRI

• Published in: NMR in biomedicine Vol. 26; no. 2; pp. 151 - 163
• Main Authors: Bokacheva, Louisa, Kotedia, Khushali, Reese, Megan, Ricketts, Sally-Ann, Halliday, Jane, Le, Carl H, Koutcher, Jason A, Carlin, Sean
• Format: Journal Article
• Language: English
• Published: 01.02.2013
• Subjects: Actin
• ISSN: 0952-3480; 1099-1492
• DOI: 10.1002/nbm.2830

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 7T, as well as super(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 (3mg/kg per dose daily) or vehicle (dosed daily), with follow-up imaging performed 2h 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 super(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 super(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 super(2)), the fraction of smooth muscle actin-positive vessels (80-87%) and the intercapillary distance (0.17mm) were similar in cediranib- and vehicle-treated groups. The fraction of perfused blood vessels in cediranib-treated tumors (81 plus or minus 7%) was lower than that in vehicle controls (91 plus or minus 3%, p=0.02). The necrotic fraction was slightly higher in cediranib-treated rats (34 plus or minus 12%) than in controls (26 plus or minus 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. Copyright copyright 2012 John Wiley & Sons, Ltd. Colorectal HT29 tumors treated with cediranib (AstraZeneca), a small-molecule vascular endothelial growth factor receptor inhibitor, for 48h, and vehicle controls were studied with dynamic contrast-enhanced and diffusion-weighted MRI. The treated tumors showed a significant decrease in K super(trans), a trend towards lower v sub(e) and unchanged apparent diffusion coefficient values. super(18)F-fluoromisonidazole positron emission tomography showed a significant post-treatment decrease in the mean tumor standardized uptake value. Treated tumors showed unchanged microvascular density, but a significantly lower fraction of perfused vessels. Short-term administration of cediranib appears to decrease tumor perfusion/permeability without changing vessel morphology.