Abstract
The effect of a human vascular endothelial growth factor antibody on the vasculature of human tumor grown in rat brain was studied. Using dynamic contrast-enhanced magnetic resonance imaging, the effects of intravenous bevacizumab (Avastin; 10 mg/kg) were examined before and at postadministration times of 1, 2, 4, 8, 12 and 24 h (N = 26; 4-5 per time point) in a rat model of orthotopic, U251 glioblastoma (GBM). The commonly estimated vascular parameters for an MR contrast agent were: (i) plasma distribution volume (v(p) ), (ii) forward volumetric transfer constant (K(trans) ) and (iii) reverse transfer constant (k(ep) ). In addition, extracellular distribution volume (V(D) ) was estimated in the tumor (V(D-tumor) ), tumor edge (V(D-edge) ) and the mostly normal tumor periphery (V(D-peri) ), along with tumor blood flow (TBF), peri-tumoral hydraulic conductivity (K) and interstitial flow (Flux) and tumor interstitial fluid pressure (TIFP). Studied as % changes from baseline, the 2-h post-treatment time point began showing significant decreases in v(p) , V(D-tumor,) V(D-edge) and V(D-peri) , as well as K, with these changes persisting at 4 and 8 h in v(p) , K, V(D-tumor, -edge) and (-peri) (t-tests; p < 0.05-0.01). Decreases in K(trans) were observed at the 2- and 4-h time points (p < 0.05), while interstitial volume fraction (v(e) ; = K(trans) /k(ep) ) showed a significant decrease only at the 2-h time point (p < 0.05). Sustained decreases in Flux were observed from 2 to 24 h (p < 0.01) while TBF and TIFP showed delayed responses, increases in the former at 12 and 24 h and a decrease in the latter only at 12 h. These imaging biomarkers of tumor vascular kinetics describe the short-term temporal changes in physical spaces and fluid flows in a model of GBM after Avastin administration.