Comparison of the antivascular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents

Abstract

TZT-1027 (Soblidotin), a microtubule-depolymerizing agent exerts both a direct cytotoxic activity against cancer cells and an indirect antivascular activity against tumor vascular endothelial cells. We compared both activities of TZT-1027 with those of various anticancer agents having different mechanisms of action, including vinca alkaloids, a vascular targeting agent, a taxane and nonmicrotubule-binding agents. In the MTT assay, TZT-1027 most potently inhibited the growth of both murine colon C26 cancer cells and human umbilical vein endothelial cells, implying its potent antivascular activity against tumor vasculature in addition to its cytotoxic activity against cancer cells. Treatment with 0.1 microg/ml TZT-1027 significantly enhanced vascular permeability in human umbilical vein endothelial cell monolayers and a single intravenous administration of 2 mg/kg TZT-1027 significantly reduced the perfusion of Colon26 tumors implanted into mice, with efficacies superior to vinca alkaloids and comparable to a known vascular targeting agent. These results strongly suggest that TZT-1027 exerts marked antivascular activity. Next, to clarify the mechanism of the antivascular activity, we have taken a novel approach, and analyzed the relationships among human umbilical vein endothelial cells cytotoxicity, vascular permeability and tumor perfusion, on the basis of efficacies of each agent. Analyses revealed strong and significant correlations, and indicated that the vascular endothelial cell damage leads to endothelial barrier dysfunction and, thereby, tumor vascular shutdown. In summary, TZT-1027 was verified to have not only an excellent cytotoxic activity, but also an attractive antivascular activity through the induction of damage to vascular endothelial cells. We believe that these dual activities may make TZT-1027 useful for treating solid tumors.