Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging

Purpose: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. Materials and Methods: Changes in kinetic DCE-MRI parameters (transfer constant [K(trans)] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m(2). Results: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor K(trans) was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor K(trans) in six of 16 patients treated at greater than or equal to 52 mg/m(2), with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle K(trans) or in kidney AUC in group analysis of the clinical data. Conclusion: CA4P acutely reduces K(trans) in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.