Combretastatin A-4 Phosphate Affects Tumor Vessel Volume and Size Distribution as Assessed Using MRI-Based Vessel Size Imaging

Purpose: Combretastatin A-4 disodium phosphate (CA4P) is a promising vascular disrupting agent (VDA) in clinical trials. As CA4P acts on dividing endothelial cells, we hypothesize that CA4P affects vessels of certain sizes. The aim of this study was to evaluate the effect of CA4P by the MRI-based vessel size imaging (VSI). Experimental Design: C3H mammary carcinomas were grown to 200 mm3 in the right rear foot of female CDF1 mice. A control group of mice received no treatment, and a treatment group had CA4P administered intraperitoneally at a dose of 250 mg/kg. VSI was conducted on a 3 Tesla MR scanner to estimate the tumor blood volume (ζ0) and mean vessel radius (R). Vascularization was also estimated histologically by endothelial and Hoechst 33342 staining. Results: ζ0 and R showed different spatial heterogeneity. Tumor median and quartile values of ζ0 were all significantly reduced by about 35% in the CA4P-treated group as compared with the control group, and the median and upper quartile of R were significantly increased. Histograms of ζ0 and R showed a general decrease in ζ0 following treatment, and values of R in a certain range (≈20–30 μm) were decreased in the treatment group. The drug-induced change in ζ0 was in agreement with histology and our previous dynamic contrast enhanced MRI (DCE-MRI) data. Conclusions: Tumor blood volume and mean vessel radius showed a clear response following treatment with CA4P. VSI may prove valuable in estimation of tumor angiogenesis and prediction of response to VDAs. Clin Cancer Res; 18(23); 6469–77. ©2012 AACR.