Combretastatin A-4 phosphate affects tumor vessel volume and size distribution as assessed using MRI-based vessel
Thomas Nielsen1, Lise Bentzen, Michael Pedersen
1Department of Experimental Clinical Oncology, Danish National Research Foundations Center of Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus, Denmark. thomas@oncology.dk
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 mm(3) in the right rear foot of female CDF(1) 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 (ζ(0)) and mean vessel radius (R). Vascularization was also estimated histologically by endothelial and Hoechst 33342 staining.
Results:
ζ(0) and R showed different spatial heterogeneity. Tumor median and quartile values of ζ(0) 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 ζ(0) and R showed a general decrease in ζ(0) following treatment, and values of R in a certain range (≈20-30 μm) were decreased in the treatment group. The drug-induced change in ζ(0) 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.
Insights
Combretastatin A-4 disodium phosphate (CA4P) significantly reduced tumor blood volume and altered mean vessel radius in mice. Vessel size imaging (VSI) shows promise for predicting response to vascular disrupting agents (VDAs).
Area of Science:
- Oncology
- Medical Imaging
- Pharmacology
Background:
- Combretastatin A-4 disodium phosphate (CA4P) is a vascular disrupting agent (VDA) investigated in clinical trials.
- CA4P targets dividing endothelial cells, suggesting size-dependent vascular effects.
- Vessel size imaging (VSI) is a novel MRI technique to assess vascular characteristics.
Purpose of the Study:
- To evaluate the effect of CA4P on tumor vasculature using MRI-based VSI.
- To investigate the relationship between CA4P treatment and changes in tumor blood volume and vessel radius.
Main Methods:
- C3H mammary carcinomas were induced in mice.
- CA4P was administered intraperitoneally at 250 mg/kg.
- VSI on a 3 Tesla MR scanner estimated tumor blood volume (ζ(0)) and mean vessel radius (R).
- Histological analysis confirmed vascularization.
Main Results:
- CA4P treatment significantly reduced tumor blood volume (ζ(0)) by approximately 35%.
- The median and upper quartile of mean vessel radius (R) were significantly increased post-treatment.
- Histograms revealed decreased ζ(0) and a reduction in vessel radii within the 20-30 μm range.
Conclusions:
- CA4P treatment demonstrably impacts tumor blood volume and mean vessel radius.
- VSI is a valuable tool for assessing tumor angiogenesis.
- VSI may aid in predicting patient response to VDAs.
