Evaluation of tumor microvascular response to brivanib by dynamic contrast-enhanced 7-T MRI in an orthotopic xenograft model of hepatocellular carcinoma.
OBJECTIVE
The purpose of this article is to evaluate the antiangiogenic effects of brivanib using dynamic contrast-enhanced MRI (DCE-MRI) in an orthotopic mouse model of human hepatocellular carcinoma (HCC).


METHODS
With human HCC (HepG2 cell line) orthotopic nude mouse xenografts, brivanib was administered orally to the treatment group, and the vehicle was administered to the control group for 14 days. DCE-MRI was performed before the start of the therapy and 7 and 14 days after the start of therapy. Treatment-induced changes in tumor volume and microvessel density (MVD) assessed by CD31 immunohistochemistry were analyzed. Perfusion parameters, including volume transfer constant between blood plasma and extravascular extracellular space (K(trans)), fractional extravascular extracellular space per unit volume of tissue (ve), and rate constant between extravascular extracellular space and blood plasma (Kep), were calculated using the two-compartment model.


RESULTS
Brivanib shows potent antitumor activity in tumor volume. The mean (± SD) MVD of the tumors was statistically significantly lower in the brivanib-treated group (40.8 ± 17.3 vessels/field) than in the control group (55.2 ± 9.05 vessels/field) (p < 0.05). In the control group, the K(trans) value increased statistically significantly between the baseline and 14 days after treatment (p = 0.048). In the brivanib-treated group, the K(trans) and ve values decreased statistically significantly between baseline and 7 days after treatment (p = 0.024 and p = 0.031, respectively) and between baseline and 14 days after treatment (p = 0.043 and p = 0.018, respectively). The difference between the K(trans) and ve values between baseline and 14 days after treatment showed a statistically significant difference between the two groups (p = 0.004 and p = 0.034, respectively).


CONCLUSIONS
DCE-MRI is feasible in the orthotopic mouse model of human HCC, and it can noninvasively monitor brivanib-induced changes in tumor microvasculature.
1 Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.
Kyoung Doo
KD
Song
Dongil
D
Choi
Jung Hee
JH
Lee
Geun Ho
GH
Im
Jehoon
J
Yang
Jae-Hun
JH
Kim
Won Jae
WJ
Lee
D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D014227:Triazines; C509922:brivanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000409:Alanine