Abstract 1317: Dose-dependent effects of bevacizumab on human HCC xenografts
Authors: Hartono Septian , Koh Tong San , Ng Quan Sing , Ong Richard , Huynh The Hung , Martarello Laurent , Thng Choon Hua 
Published: August 2012

Abstract
Introduction: Bevacizumab has demonstrated positive clinical treatment effect and is currently approved for treatment of colorectal carcinoma and NSCLC in combination with standard chemotherapy. Preclinical studies have shown decrease in microvascular density. We aim to determine if DCE-MRI is a sensitive enough technique to detect changes in fractional intravascular volume after administration of a single dose of bevacizumab. Materials and Methods: Mice: Twenty-seven male BALB/c mice (6 weeks old, 24 ± 2g) formed the study population & were under 1-2 % isoflurane during the scanning. They were implanted with human-derived HCC xenograft line, sensitive to bevacizumab therapy. Two dose levels were investigated: low dose (n = 4) at 1 mg/kg and high dose (n=8) at 10 mg/kg. Mice were scanned at baseline, day 1 and 5 after therapy. Fifteen control mice were similarly imaged after receiving omalizumab, a human anti-IgE antibody, at 10 mg/kg. Tumors were sectioned and stained immunohistochemically to identify CD34 for quantification of MVD. DCE-MRI: MRI was performed on a 7T scanner (Bruker ClinScan, Bruker BioSpin MRI GmbH, Germany). A 3D VIBE sequence was used with following parameters: TR = 3.04 ms, TE = 1.23 ms, FOV = 36 × 36 mm, 128 × 128 matrix, 8 slices with thickness of 1 mm, & temporal resolution 2 s. Five sets of baseline images were acquired with ≤ = 6° & 14°. It was followed by a dynamic sequence of 130 sets of images (α = 14°). A dose of 100 µL of Gd-DOTA (Dotarem, Guerbet SA, France) at 1 mmol/kg was injected through the tail vein after the first set of dynamic images. Data Processing: Region of interests corresponding to the xenograft and major artery were manually outlined. Blood volume was derived from the standard two-compartment model. Results: Baseline blood volume for the control group was 7.32 ± 3.47 %. The values were 9.67 ± 1.72 % for the group treated with bevacizumab 1 mg/kg and 10.02 ± 3.85 % for the group dosed with bevacizumab 10 mg/kg. A reduction of 52.69 ± 24.77 % in blood volume at Day 1 and 75.25 ± 12.58 % at Day 5 was observed in the higher dose group, while a reduction of 6.10 ± 31.86 % at Day 1 and 56.99 ± 9.18 % at Day 5 was observed in the lower dose group. An increase of 29.31 ± 66.84 % at Day 1 was observed in the control group. There is a good correlation between percentage of MVD derived by CD34 staining with percentage of blood volume derived by the two-compartment model (r = 0.806, p = 0.0002). Conclusion: The results showed that the effects of bevacizumab are dose-related. A more gradual drop of blood volume was observed in group treated with bevacizumab 1 mg/kg. On the other hand, a steep and immediate drop of blood volume was observed in group treated with bevacizumab 10 mg/kg. The results suggested potential of DCE-MRI as a sensitive biomarker of MVD and as a reliable non-destructive testing method for time course observation of MVD changes in animals. This facilitates translation and clinical application to early time points after anti-angiogenic therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1317. doi:1538-7445.AM2012-1317