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An in vivo role for R ho kinase activation in the tumour vascular disrupting activity of combretastatin A ‐4 3‐ O ‐phosphate
Author(s) -
Williams L J,
Mukherjee D,
Fisher M,
ReyesAldasoro C C,
Akerman S,
Kanthou C,
Tozer G M
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12817
Subject(s) - hydralazine , in vivo , combretastatin , rho associated protein kinase , pharmacology , chemistry , vasodilation , necrosis , medicine , cancer research , kinase , pathology , blood pressure , microbiology and biotechnology , biology , biochemistry , microtubule , tubulin
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 .