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5,6-dimethylxanthenone-4-acetic acid (DMXAA),a potent vascular disrupting agent,selectively destroys established tumor vasculature,causing a rapid collapse in blood flow that ultimately leads to inhibition of tumor growth.Here,we demonstrate that p38 MAPK is critically involved in DMXAA-induced cytoskeleton reorganization in endothelial cells and TNF-α production in macrophages,both of which were essential for DMXAA-induced vascular disruption.Inhibition of p38 MAPK significantly attenuated DMXAA-induced actin cytoskeleton reorganization in human umbilical vein endothelial cells and TNF-α production in macrophages.In vivo,p38 MAPK inhibition attenuated the immediate reduction in tumor blood flow induced by DMXAA treatment (<30 min) by inhibiting actin cytoskeleton reorganization in tumor vascular endothelial cells,and blunted the long-lasting (>4 h) DMXAA-induced shutdown of the tumor vasculature by inhibiting intratumoral TNF-α production.These results indicate that p38 MAPK plays a critical role in DMXAA-induced endothelial cell cytoskeleton reorganization and TNF-α production,thus regulating DMXAA-induced antitumor activity.