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Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues
G M Tozer1, V E Prise, J Wilson
1Tumor Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Abstract:
The potential for tumor vascular-targeting by using the tubulin destabilizing agent disodium combretastatin A-4 3-0-phosphate (CA-4-P) was assessed in a rat system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The early vascular effects of CA-4-P were assessed in the s.c. implanted P22 carcinosarcoma and in a range of normal tissues. Blood flow was measured by the uptake of radiolabeled iodoantipyrine, and quantitative autoradiography was used to measure spatial heterogeneity of blood flow in tumor sections. CA-4-P (100 mg/kg i.p.) caused a significant increase in mean arterial blood pressure at 1 and 6 h after treatment and a very large decrease in tumor blood flow, which-by 6 h-was reduced approximately 100-fold. The spleen was the most affected normal tissue with a 7-fold reduction in blood flow at 6 h. Calculations of vascular resistance revealed some vascular changes in the heart and kidney for which there were no significant changes in blood flow. Quantitative autoradiography showed that CA-4-P increased the spatial heterogeneity in tumor blood flow. The drug affected peripheral tumor regions less than central regions. Administration of CA-4-P (30 mg/kg) in the presence of the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester, potentiated the effect of CA-4-P in tumor tissue. The combination increased tumor vascular resistance 300-fold compared with less than 7-fold for any of the normal tissues. This shows that tissue production of nitric oxide protects against the damaging vascular effects of CA-4-P. Significant changes in tumor vascular resistance could also be obtained in isolated tumor perfusions using a cell-free perfusate, although the changes were much less than those observed in vivo. This shows that the action of CA-4-P includes mechanisms other than those involving red cell viscosity, intravascular coagulation, and neutrophil adhesion. The uptake of CA-4-P and combretastatin A-4 (CA-4) was more efficient in tumor than in skeletal muscle tissue and dephosphorylation of CA-4-P to CA-4 was faster in the former. These results are promising for the use of CA-4-P as a tumor vascular-targeting agent.
Insights
Disodium combretastatin A-4 3-0-phosphate (CA-4-P) effectively targets tumor vasculature, significantly reducing blood flow and causing necrosis. Nitric oxide inhibition potentiates CA-4-P
Area of Science:
- Pharmacology
- Oncology
- Vascular Biology
Background:
- Tumor vascular-targeting agents offer a strategy to induce tumor cell death by disrupting established tumor vasculature.
- Disodium combretastatin A-4 3-0-phosphate (CA-4-P) is a tubulin destabilizing agent with potential for vascular targeting.
Purpose of the Study:
- To assess the efficacy of CA-4-P as a tumor vascular-targeting agent in a rat model.
- To investigate the early vascular effects of CA-4-P on tumor and normal tissues.
- To explore the role of nitric oxide in modulating CA-4-P's vascular effects.
Main Methods:
- Tumor blood flow was measured using radiolabeled iodoantipyrine uptake and quantitative autoradiography in P22 carcinosarcoma-bearing rats.
- Vascular resistance was calculated, and the effects of CA-4-P were assessed alone and in combination with a nitric oxide synthase inhibitor.
- In vitro tumor perfusion studies were conducted to investigate CA-4-P's mechanisms of action.
Main Results:
- CA-4-P (100 mg/kg) significantly reduced tumor blood flow by approximately 100-fold within 6 hours, leading to increased spatial heterogeneity.
- The spleen was the most affected normal tissue, with a 7-fold reduction in blood flow.
- Combining CA-4-P with a nitric oxide synthase inhibitor potentiated tumor vascular resistance significantly more than in normal tissues, indicating nitric oxide's protective role.
Conclusions:
- CA-4-P demonstrates potent tumor vascular-targeting activity, leading to substantial reductions in tumor blood flow and increased vascular resistance.
- The study suggests that tissue production of nitric oxide plays a protective role against the vascular-damaging effects of CA-4-P.
- CA-4-P's mechanism of action involves pathways beyond red blood cell viscosity, intravascular coagulation, and neutrophil adhesion, with efficient uptake and activation in tumor tissue.