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.
Department of Radiology, University of California, San Francisco, CA 94143, USA.
Hans-Juergen
HJ
Raatschen
Yanjun
Y
Fu
Robert C
RC
Brasch
Hubertus
H
Pietsch
David M
DM
Shames
Benjamin M
BM
Yeh
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