Korean J Radiol.  2011 Oct;12(5):602-610. 10.3348/kjr.2011.12.5.602.

Evaluation of Antiangiogenic Effects of a New Synthetic Candidate Drug KR-31831 on Xenografted Ovarian Carcinoma Using Dynamic Contrast Enhanced MRI

• Yang J
• Kim JH
• Im GH
• Heo H
• Yoon S
• Lee J
• Lee JH
• Jeon P

• KMID: 1116446
• DOI: http://doi.org/10.3348/kjr.2011.12.5.602

Abstract

OBJECTIVE
The purpose of this research was to investigate the anti-angiogenic inhibitory effect of KR-31831, a newly developed anti-angiogenic agent, on an in vivo human ovarian carcinoma model using dynamic contrast-enhanced (DCE) MRI.
MATERIALS AND METHODS
Xenografted ovarian tumors were established by subcutaneous injection of SKOV3 cells into mice. The mice were treated daily with KR-31831 at 50 mg/kg for 21 days. Tumor tissues were excised corresponding to the DCE-MRI sections for evaluation of MVD with CD31 immunohistochemistry. All in vivo MRIs were performed on a 7.0 Tesla micro-MRI System. DCE-MRI was acquired prior to initiating treatment with KR-31831 and again on days 3 and 21 after treatment. The permeability parameters (Ktrans, ve, and vp) were estimated using a pharmacokinetic model.
RESULTS
Qualitatively, the Ktrans parametric mapping showed different changes before and after treatment with KR-31831 in the treatment group. For quantification of this change, the median of Ktrans values were compared before and after treatments in the control and KR-31831-treated groups. A non-parametric statistical test (Wilcoxon signed-rank test) showed decreasing Ktrans values on day 21 compared to days 0 and 3 in the KR-31831-treated group (p < 0.05), whereas there was no significant difference in the control group (p = 0.84).
CONCLUSION
Our results suggest that DCE-MRI can be a useful tool by which to evaluate the anti-angiogenic effect of KR-31831 on a xenografted human ovarian carcinoma model.

Keyword

Angiogenesis; Dynamic contrast-enhanced MRI; Microvascular density; KR-31831; VEGF

MeSH Terms

Angiogenesis Inhibitors/*pharmacology
Animals
Benzopyrans/*pharmacology
Cell Line, Tumor
*Contrast Media
Female
Humans
Imidazoles/*pharmacology
Immunohistochemistry
*Magnetic Resonance Imaging
Mice
Mice, Inbred BALB C
Mice, Nude
Microvessels/pathology
Neoplasm Transplantation
Ovarian Neoplasms/*blood supply/pathology

Figure

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  Fig. 1 Determination of arterial input function. A. Manually-defined arterial input function voxels by visual inspection of concentration time curves are shown in red. B. Representative concentration profile of arterial input function defined in A.

• 

  Fig. 2 Non-linear fitting using pharmacokinetic modeling method. A. Manually-defined tumor region is shown in blue. B. Representative concentration profile of tumor region (blue circle), and fitted data (red dot-line) using non-linear fitting method.

• 

  Fig. 3 Pharmacokinetic parametric mapping in control and KR-31831-treated mice on days 1, 3, and 21. A. Ktrans map for control mice. B. Ktrans map for KR-31831-treated mice. Color schema ranges from 0 (blue) to 0.02 (red).

• 

  Fig. 4 Wilcoxon signed-rank test (Ktrans parameter) before and after treatments in control and KR-31831-treated groups. *p < 0.05

• 

  Fig. 5 Representative immunohistochemical analysis of microvessel density of xenografted SKOV3 tumor tissues obtained from control (A) and KR-31831-treated groups (B) in accordance with dynamic contrast-enhanced MRI sections at end time point of treatment. Vessels show dark brown color. Scale bar, 100 µm. Microvessel density was quantified and averaged in five random fields without necrosis per tumor at 200X magnification. Note microvessel density/field (C) was significantly reduced in tumor tissue from KR-31831 treatment group (14.9 ± 4.0) compared with control group (18.6 ± 5.2). p < 0.05. Error bars, SD.

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