Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues.

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.

• Authors: G M Tozer, V E Prise, J Wilson, R J Locke, B Vojnovic, M R Stratford, M F Dennis, D J Chaplin
• Journal: Cancer research (Cancer Res) Vol. 59 Issue 7 Pg. 1626-34 (Apr 01 1999) ISSN: 0008-5472 [Print] United States
• PMID: 10197639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Stilbenes
• fosbretabulin
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Blood Pressure (drug effects)
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neoplasms, Experimental (blood supply, drug therapy)
• Phosphorylation
• Rats
• Regional Blood Flow (drug effects)
• Stilbenes (metabolism, pharmacology)
• Vascular Resistance (drug effects)