In vivo monitoring of angiogenesis inhibitory treatment effects by dynamic contrast-enhanced computed tomography in a xenograft tumor model.
OBJECTIVE
To evaluate the potential of dynamic CT enhanced by iohexol or a novel macromolecular contrast agent, PEG12000-Gen4-triiodo, to monitor microvascular changes in tumors treated with the angiogenesis inhibitor bevacizumab.


METHODS
Ten female nude rats with MDA-MB 435 xenograft tumors were treated with 1 mg intraperitoneal bevacizumab when tumors reached 1 cm diameter and, for 4 rats, treated again 7 days later. Just before and 24 hours after the first injection of anti-VEGF antibody, the tumors were imaged by dynamic CT scans enhanced with PEG12000-Gen4-triiodo (n = 3 rats) or iohexol (n = 3 rats). The other 4 rats underwent dynamic CT scans enhanced with PEG12000-Gen4-triiodo just before and 24 hours after the second injection of anti-VEGF antibody. Microvascular leakiness (K(PS)) was calculated for the tumors using a 2-compartment tissue model.


RESULTS
PEG12000-Gen4-triiodo-enhanced CT scans showed progressive reductions in K(PS) from day 1 to 2 to 9 (from 2.55 to 1.27 to 0.69 microL min(-1) cm(-3), respectively, P < 0.005 for each comparison of day 1-2 and day 2-9). No significant difference was seen in the K(PS) estimates derived from iohexol-enhanced CT scans obtained before or after treatment (276 vs. 223.8 microL min(-1) cm(-3), respectively, P = 0.54). The microvascular leak (K(PS)) was significantly larger for iohexol than for PEG12000-Gen4-triiodo-enhanced CT, P < 0.05.


CONCLUSIONS
Dynamic macromolecular contrast-enhanced CT can be used to monitor serial decreases in tumor microvessel leakiness induced by repeated doses of an angiogenesis inhibitor drug.
Raatschen
Hans-Juergen
HJ
Department of Radiology, University of California, San Francisco, CA 94143, USA.
Fu
Yanjun
Y
Brasch
Robert C
RC
Pietsch
Hubertus
H
Shames
David M
DM
Yeh
Benjamin M
BM
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D050091:Dendrimers; D005240:Feasibility Studies; D005260:Female; D007472:Iohexol; D011092:Polyethylene Glycols; D011856:Radiographic Image Enhancement / Q000379:methods*; D051381:Rats; D011923:Rats, Nude; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050091:Dendrimers; C507127:PEG12000-Gen4-triiodo; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D011092:Polyethylene Glycols; D007472:Iohexol