Combretastatin A-4 phosphate affects tumor vessel volume and size distribution as assessed using MRI-based vessel size imaging.
OBJECTIVE
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).


METHODS
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.
Department of Experimental Clinical Oncology, Danish National Research Foundations Center of Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus, Denmark. thomas@oncology.dk
Thomas
T
Nielsen
Lise
L
Bentzen
Michael
M
Pedersen
Trine
T
Tramm
Paul F J W
PF
Rijken
Johan
J
Bussink
Michael R
MR
Horsman
Leif
L
Østergaard
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000175:diagnosis* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000188:drug therapy; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C058728:fosbretabulin