Vascular disrupting effect of combretastatin A-4 phosphate with inhibition of vascular endothelial cadherin in canine osteosarcoma-xenografted mice.

Combretastatin A-4 phosphate (CA4P) induces tumor necrosis by selectively inhibiting tumor blood flow. However, the detailed mechanisms by which CA4P selectively disrupts tumor blood vessels are not well understood. Our previous study indicated that the selective blocking effect of CA4P might be related to a vascular endothelial cadherin (VE-cadherin) dysfunction in the tumor vasculature. In this study, we evaluated the vascular disrupting effect of CA4P on canine osteosarcomas xenografted into mice, focusing on VE-cadherin. Even though 30 mg/kg CA4P only partially inhibited blood flow in the xenografted tumor, a combination of an anti-VE-cadherin neutralizing antibody and 30 mg/kg CA4P inhibited most of the tumor blood flow. In addition, the combination of antibody and drug significantly inhibited tumor growth compared to the control. These results strongly suggested a relationship between the expression of VE-cadherin in tumor blood vessels and the selective blocking mechanisms of CA4P.