An in vivo role for Rho kinase activation in the tumour vascular disrupting activity of combretastatin A-4 3-O-phosphate

作者：Williams L J; Mukherjee D; Fisher M; Reyes Aldasoro C C; Akerman S; Kanthou C; Tozer G M^*

来源：British Journal of Pharmacology, 2014, 171(21): 4902-4913.

DOI：10.1111/bph.12817

Background and PurposeCombretastatin 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 Rho/Rho kinase (ROCK) is fundamental to the effects of this drug in vivo. %26lt;br%26gt;Experimental ApproachMouse models of human colorectal carcinoma (SW1222 and LS174T) were used. Effects of the ROCK inhibitor, Y27632, 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. %26lt;br%26gt;Key ResultsY27632 caused a rapid drop in blood flow in SW1222 tumours, with recovery by around 3h, which was paralleled by MABP changes. Y27632 pretreatment reduced CA4P-induced ROCK activation and partially blocked CA4P-induced tumour vascular effects, in both tumour types. Y27632 also partially inhibited CA4P-induced tumour necrosis and was associated with reduced immune cell infiltration in SW1222 tumours. Hydralazine caused a similar hypotensive effect as Y27632 but had no protective effect against CA4P treatment. %26lt;br%26gt;Conclusions and ImplicationsThese results demonstrate that ROCK activity is critical for full manifestation of the vascular activity of CA4Pin vivo, providing the evidence for pharmacological intervention to enhance the anti-tumour efficacy of CA4P and related VDAs.

• 出版日期2014-11