The effects of the vascular disrupting agents combretastatin A-4 disodium phosphate, 5,6-dimethylxanthenone-4-acetic acid and ZD6126 in a murine tumour: A comparative assessment using MRI and MRS

Abstract

The aim of this study was to use magnetic resonance (MR) techniques to non-invasively compare the effects of the three leading vascular disrupting agents, namely combretastatin A-4 disodium phosphate (CA4DP), 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and ZD6126. A C3H mouse mammary carcinoma grown in the right rear foot of female CDF1 mice was used and treatments performed when tumours had reached 200 mm³ in volume. Drugs were prepared fresh before each experiment and intraperitoneally injected into restrained non-anaesthetised mice. Tumour response was evaluated using ³¹P-MR spectroscopy and T1- and T2- weighted imaging with a 7-Tesla, horizontal bore magnet, before and up to 24 hours after treatment. All three drugs significantly decreased bioenergetic status and pH, and did so in a time and dose dependent fashion, but there were differences; the decrease by CA4DP occurred more rapidly than for DMXAA or ZD6126, while DMXAA had a narrow window of activity compared to CA4DP and ZD6126. Changes in T1 weighted images for all three agents suggested a dose dependent increase in tumour oedema within three hours after treatment, consistent with an increase in vessel permeability. Using T2 weighted images there was some evidence of haemaorrhagic necrosis by DMXAA, but such necrosis was limited following treatment with CA4DP or ZD6126.