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Background and Purpose  Combretastatin  A ‐4 3‐  O  ‐phosphate ( CA4P ) is in clinical trial as a tumour vascular disrupting agent ( VDA ) but the cause of blood flow disruption is unclear. We tested the hypothesis that activation of  R ho/ R ho kinase ( ROCK ) is fundamental to the effects of this drug  in vivo .    Experimental Approach  Mouse models of human colorectal carcinoma ( SW 1222 and  LS174T ) were used. Effects of the  ROCK  inhibitor,  Y 27632, alone or in combination with  CA4P , on  ROCK  activity, vascular function, necrosis and immune cell infiltration in solid tumours were determined. Mean arterial  BP  ( MABP ) was measured to monitor systemic interactions and the vasodilator, hydralazine, was used to control for the hypotensive effects of  Y27632 .    Key Results   Y 27632 caused a rapid drop in blood flow in  SW 1222 tumours, with recovery by around 3 h, which was paralleled by  MABP  changes.  Y 27632 pretreatment reduced  CA4P ‐induced  ROCK  activation and partially blocked  CA4P ‐induced tumour vascular effects, in both tumour types.  Y 27632 also partially inhibited  CA4P ‐induced tumour necrosis and was associated with reduced immune cell infiltration in  SW 1222 tumours. Hydralazine caused a similar hypotensive effect as  Y 27632 but had no protective effect against  CA4P  treatment.    Conclusions and Implications  These results demonstrate that  ROCK  activity is critical for full manifestation of the vascular activity of  CA4P   in vivo , providing the evidence for pharmacological intervention to enhance the anti‐tumour efficacy of  CA4P  and related  VDAs .

An in vivo role for R ho kinase activation in the tumour vascular disrupting activity of combretastatin A ‐4 3‐ O ‐phosphate