The vascular response of tumor and normal tissues in the rat to the vascular targeting agent, combretastatin A-4-phosphate, at clinically relevant doses.

The antivascular actions of disodium combretastatin A-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 carcinosarcoma after single doses of 10 or 30 mg x kg(-1). Pharmacokinetic data showed that 10 mg x kg(-1) in the rat gave a plasma exposure similar to that achieved in the clinic. Blood flow rate to the tumor and normal tissues was measured using the uptake of radiolabelled iodoantipyrine (IAP). Quantitative autoradiography was used to determine changes in spatial distribution of tumor blood flow. Both doses caused an increase in mean arterial blood pressure (MABP) and a reduction in heart rate 1 h after treatment. Blood flow rate to the tumor decreased to below 15% of control for both doses at 1 h, whereas the normal tissues were much less affected. A further reduction (to 2% of control at 6 h) was found for 30 mg x kg(-1). Recovery was essentially complete by 24 h for both doses. Vascular resistance increased 80-fold in tumor at 6 h after 30 mg x kg(-1), compared with a maximum 5-fold increase in normal tissues. Analysis of the spatial distribution of tumor blood flow illustrated an overall reduction in all areas of the tumor at 1 h after 10 mg x kg(-1), with a tendency for blood flow in the peripheral regions of the tumor to recover more quickly than in central regions. Tumor blood flow reduction was related to vascular damage including vessel distension, coagulation and haemorrhage, and tumor cell damage culminating in necrosis. No pathology was evident in any of the normal tissues following treatment. The data provide an insight into the mechanisms underlying tissue blood flow changes occurring after clinically relevant doses of CA-4-P. It is currently being used to aid interpretation of pharmacodynamic data obtained from phase I/II clinical trials of CA-4-P and is relevant for future drug development in this area.