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

The potential for tumor vascular-targeting by using the tubulin destabilizi ng agent disodium combretastatin A-4 3-O-phosphate (CA-4-P) was assessed in a rat system. This approach aims to shut down the established tumor vascul ature, leading to the development of extensive tumor cell necrosis, The ear ly vascular effects of CA-4-P were assessed in the s.c. implanted P22 carci nosarcoma 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 p ressure at 1 and 6 h after treatment and a very large decrease in tumor blo od flow, which-by 6 h-was reduced approximately 100-fold. The spleen was th e 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 hete rogeneity in tumor blood flow. The drug affected peripheral tumor regions l ess than central regions. Administration of CA-4-P (30 mg/kg) in the presen ce 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 in creased tumor vascular resistance 300-fold compared with less than 7-fold f or any of the normal tissues. This shows that tissue production of nitric o xide protects against the damaging vascular effects of CA-4-P. Significant changes in tumor vascular resistance could also be obtained in isolated tum or perfusions using a cell-free perfusate, although the changes were much l ess than those observed in vivo. This shows that the action of CA-4-P inclu des mechanisms other than those involving red cell viscosity, intravascular coagulation, and neutrophil adhesion. The uptake of CA-4-P and combretasta tin A-4 (CA-4) was more efficient in tumor than in skeletal muscle tissue a nd dephosphorylation of CA-4-P to CA-4 was faster in the former. These resu lts are promising for the use of CA-4-P as a tumor vascular-targeting agent .