Treatment of rodent liver tumor with combretastatin a4 phosphate: noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology.
OBJECTIVE
To document tumoricidal events after intravenous administration of a vascular targeting agent combretastatin A-4-phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.


METHODS
Thirty rhabdomyosarcomas of 8 to 14 mm in diameter were obtained 16 days after implantation in liver lobes of 15 rats. Using a 1.5T magnet and a 4-channel wrist coil, T2-weighted imaging (T2WI), pre- and postcontrast T1-weighted imaging (T1WI), diffusion-weighted imaging (DWI), and dynamic susceptibility imaging (DSI) with relative blood volume (rBV) and flow (rBF) maps were acquired at baseline, 1 hour, 6 hours, and 48 hours after iv injection of CA4P at 10 mg/kg and vehicle in 9 treated and 6 control rats, respectively. In vivo data including signal intensity (SI), tumor volume, apparent diffusion coefficient (ADC), rBV, and rBF were correlated with ex vivo microangiographic and histopathologic findings.


RESULTS
CA4P-treated tumors (n = 18) grew slower than those (n = 12) of controls (P < 0.05), with vascular shutdown evident on CE-T1WI at 1 hour but more prominent at 6 hours. However, enhanced rim occurred in the periphery 48 hours after treatment, indicating neovascularization. ADC map enabled distinction between necrotic and viable tumors. DSI-derived tumoral rBV and rBF decreased significantly at 1 hour through 6 hours and partly recovered at 48 hours. SI-time curve reflected diverse therapeutic responses between tumor and liver. MRI findings were verified by ex vivo techniques.


CONCLUSIONS
Clinical MRI allowed monitoring of CA4P-related vascular shutdown, necrosis, and neovascularization of liver tumors in rats. Single dose of CA4P seemed insufficient for tumor eradication because of evident peripheral residue and recurrence.
Wang
Huaijun
H
Department of Medical Diagnostic Science, University of Leuven, Leuven, Belgium.
Sun
Xihe
X
Chen
Feng
F
De Keyzer
Frederik
F
Yu
Jie
J
Landuyt
Willy
W
Vandecaveye
Vincent
V
Peeters
Ronald
R
Bosmans
Hilde
H
Hermans
Robert
R
Marchal
Guy
G
Ni
Yicheng
Y
D000465:Algorithms; D000792:Angiography / Q000379:methods; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D003287:Contrast Media; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D018810:Magnetic Resonance Angiography / Q000379:methods*; D008297:Male; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000188:drug therapy*; D051381:Rats; D015203:Reproducibility of Results; D012208:Rhabdomyosarcoma / Q000175:diagnosis / Q000188:drug therapy; D012680:Sensitivity and Specificity; D013223:Statistics as Topic; D013267:Stilbenes / Q000008:administration & dosage*; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D013267:Stilbenes; C058728:fosbretabulin