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

SM Galbraith, RJ Maxwell, MA Lodge… - Journal of clinical …, 2003 - pfeifer.phas.ubc.ca
SM Galbraith, RJ Maxwell, MA Lodge, GM Tozer, J Wilson, NJ Taylor, JJ Stirling, L Sena…
Journal of clinical oncology, 2003pfeifer.phas.ubc.ca
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 pa-rameters (transfer constant [Ktrans] and area under contrast medium-time curve
[AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I …
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 pa-rameters (transfer constant [Ktrans] 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/m2.
Results: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans 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 Ktrans in six of 16 patients treated at> 52 mg/m2, 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 Ktrans or in kidney AUC in group analysis of the clinical data.
Conclusion: CA4P acutely reduces Ktrans 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.
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