Evaluation of the anti-vascular effects of combretastatin in rodent tumours by dynamic contrast enhanced MRI

The anti-vascular effects of the tubulin binding agent, disodium combretastatin A-4 3-O-phosphate (CA-4-P), have been investigated in the rat P22 carcinosarcoma by measurements of radiolabelled iodoantipyrine uptake and dynamic contrast-enhanced MRI. The iodoantipyrine estimates of absolute tumour blood flow showed a reduction from 0.35 to 0.04 ml g^-1 min^-1 6 h after 10 mg kg^-1 CA-4-P and to <0.01 ml g^-1 min^-1 after 100 mg kg^-1. Tumour blood flow recovered to control values 24 h after 10 mg kg^-1 CA-4-P, but there was no recovery by 24 h after the higher dose. Dynamic contrast-enhanced MR images were obtained at 4.7 T, following injection of 0.1 mmol kg^-1 Gd-DTPA and analysed assuming a model arterial input function. A parameter, K^trans, which is related to blood flow rate and permeability of the tumour vasculature to Gd-DTPA, was calculated from the uptake data. K^trans showed a reduction from 0.34 to 0.11 min^-1 6 h after 10 mg kg^-1 CA-4-P and to 0.07 min^-1 after 100 mg kg^-1. Although the magnitude of changes in K^trans was smaller than that in tumour blood flow, the time course and dose-dependency patterns were very similar. The apparent extravascular extracellular volume fraction, ν_e, showed a four-fold reduction 6 h after 100 mg kg^-1 CA-4-P, possibly associated with vascular shutdown within large regions of the tumour. These results suggest that K^trans values for Gd-DTPA uptake into tumours could be a useful non-invasive indicator of blood flow changes induced by anti-vascular agents such as combretastatin.