Nagaraja TN, Elmghirbi R, Brown SL, Rey JA, Schultz L, Mukherjee A, Cabral G, Panda S, Lee IY, Sarntinoranont M, Keenan KA, Knight RA, and Ewing JR. Imaging acute effects of bevacizumab on tumor vascular kinetics in a preclinical orthotopic model of U251 glioma. NMR Biomed 2021;e4516.
NMR in biomedicine
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.
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