Vascular permeability during antiangiogenesis treatment: MR imaging assay results as biomarker for subsequent tumor growth in rats.
OBJECTIVE
To prospectively evaluate in rats the acute change in tumor vascular leakiness (K(PS)) assayed at magnetic resonance (MR) imaging after a single dose of the angiogenesis inhibitor bevacizumab as a predictive biomarker of tumor growth response after a prolonged treatment course.


METHODS
Institutional animal care and use committee approval was obtained. Seventeen female rats with implanted human breast cancers underwent dynamic albumin-(Gd-DTPA)(30)-enhanced MR imaging followed by an initial dose of bevacizumab or saline (as a control). Treatment was continued every 3rd day, for a total of four doses at five possible dose levels: 0 mg bevacizumab (n = 4 [control rats]), 0.1 mg bevacizumab (n = 3), 0.25 mg bevacizumab (n = 2), 0.5 mg bevacizumab (n = 5), and 1.0 mg bevacizumab (n = 3). A second MR imaging examination was performed 24 hours after the initial dose to enable calculation of the acute change in MR imaging-assayed leakiness, or Delta K(PS). This acute change in K(PS) at MR imaging was correlated with tumor growth response for each cancer at the completion of the 11-day treatment course. For statistical analyses, an unpaired two-tailed t test, analysis of variance, and linear regression analyses were used.


RESULTS
The MR imaging-assayed change in tumor microvascular leakiness, tested as a potential biomarker, correlated strongly with tumor growth rate (R(2) = 0.74, P < .001). K(PS) and tumor growth decreased significantly in all bevacizumab-treated cancers compared with these values in control group cancers (P < .05).


CONCLUSIONS
The MR imaging-assayed acute change in vascular leakiness after a single dose of bevacizumab was an early, measurable predictive biomarker of tumor angiogenesis treatment response.
Raatschen
Hans-Juergen
HJ
Department of Radiology, Center for Pharmaceutical and Molecular Imaging, Cardiovascular Research Institute, Comprehensive Cancer Center, University of California San Francisco, CA, USA. hans-juergen.raatschen@charite.de
Simon
Gerhard H
GH
Fu
Yanjun
Y
Sennino
Barbara
B
Shames
David M
DM
Wendland
Michael F
MF
McDonald
Donald M
DM
Brasch
Robert C
RC
D000465:Algorithms; D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D007091:Image Processing, Computer-Assisted; D016018:Least-Squares Analysis; D008279:Magnetic Resonance Imaging; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011446:Prospective Studies; D051381:Rats
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D003287:Contrast Media; D000068258:Bevacizumab; D019786:Gadolinium DTPA