Abstract：
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 Rho/Rho kinase (ROCK) is fundamental to the effects of this drug in vivo. EXPERIMENTAL APPROACH:Mouse 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. KEY RESULTS:Y27632 caused a rapid drop in blood flow in SW1222 tumours, with recovery by around 3 h, 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. 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.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Williams LJ,Mukherjee D,Fisher M,Reyes-Aldasoro CC,Akerman S,Kanthou C,Tozer GMdoi
10.1111/bph.12817subject
Has Abstractpub_date
2014-11-01 00:00:00pages
4902-13issue
21eissn
0007-1188issn
1476-5381journal_volume
171pub_type
杂志文章abstract：:1. The mechanism of the inhibitory effect of dehydroemetine on the heart was investigated using (a) the spontaneously contracting isolated guinea-pig atrial preparation and (b), the electrically driven left atrial preparation.2. Dehydroemetine decreased the rate and amplitude of contraction of spontaneously contractin...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1972.tb06897.x
更新日期：1972-12-01 00:00:00
abstract：:In recent years there has been a growing recognition of the influence of sex on brain structure and function, and in relation, on the susceptibility, prevalence and response to treatment of psychiatric disorders. Most theories and descriptions of the effects of sex on the brain are dominated by an analogy to the curre...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.12732
更新日期：2014-10-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Cholecystokinin (CCK) stimulates the release of amylase and lipase from the normal pancreas. However, it is not clear to what extent this occurs in the early stages of pancreatitis induced by biliary tract obstruction in the rat and whether CCK initiates an inflammatory cascade in this condition....
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/bjp.2008.44
更新日期：2008-04-01 00:00:00
abstract：:1. Diadenosine tetraphosphate (Ap4A) a dinucleotide stored and released from rat brain synaptic terminals presents two types of affinity binding sites in synaptosomes. When [3H]-Ap4A was used for binding studies a Kd value of 0.10 +/- 0.014 nM and a Bmax value of 16.6 +/- 1.2 fmol mg-1 protein were obtained for the hi...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb13510.x
更新日期：1993-04-01 00:00:00
abstract：:Spontaneous inhibitory postsynaptic currents (i.p.s.cs) were recorded in voltage-clamped CA1 neurones in rat hippocampal slices. The exponential decay of i.p.s.cs was prolonged by concentrations of sodium pentobarbitone as low as 50 microM. With concentrations up to 100 microM, there was no change in the amplitude or ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1985.tb10563.x
更新日期：1985-07-01 00:00:00
abstract：:1 Post-tetanic potentiation (p.t.p.) of the compound action potential in the presence of hexamethonium was observed in the isolated stellate ganglion of the hamster using extracellular postganglionic recordings. 2 The magnitude of the p.t.p. was small (less than a 20% increase) in the control solution, but increased a...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1980.tb07897.x
更新日期：1980-06-01 00:00:00
abstract：:1. The presence of an endogenous digitalis-like factor (EDLF) in the plasma of both normal and volume expanded animals is well documented. In this study we have used ouabain and bufalin as pharmacological analogues to mimic the renal effects of EDLF and to investigate whether any interaction occurs between atrial natr...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb12852.x
更新日期：1993-03-01 00:00:00
abstract：:This article discusses the background to the need for change in the reporting of experiments involving animals, including a report of a consensus meeting organised by the Basel Declaration Society and Understanding Animal Research UK that sought to Internationalise guidelines for reporting experiments involving animal...
journal_title：British journal of pharmacology
pub_type： 社论
doi：10.1111/bph.12956
更新日期：2015-05-01 00:00:00
abstract：:1. The involvement of peripheral nitric oxide (NO) in febrigenic signaling to the brain has been proposed because peripherally administered NO synthase (NOS) inhibitors attenuate lipopolysaccharide (LPS)-induced fever in rodents. However, how the unstable molecule of NO can reach the brain to trigger fever is unclear....
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705713
更新日期：2004-04-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702287
更新日期：1999-01-01 00:00:00
abstract：:Alcohol-use disorders are chronically relapsing conditions characterized by cycles of use, abstinence and relapse. The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to alcohol seeking and a key target of pharmacotherapies for relapse prevention. There has been a significant increase in...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.15160
更新日期：2020-09-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1984.tb16494.x
更新日期：1984-10-01 00:00:00
abstract：:1. Morphine-like analgesic drugs caused depression of twitches of the isolated guinea-pig ileum in response to transmural electrical stimulation. The drugs tested were the narcotic analgesics codeine, diamorphine, fentanyl, morphine, morphine-N-oxide, normorphine, oxymorphone, pethidine, phenazocine and phenoperidine ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1969.tb10580.x
更新日期：1969-10-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1982.tb09162.x
更新日期：1982-03-01 00:00:00
abstract：:1. We previously reported that substance P and insulin-like growth factor-1 (IGF-1) synergistically stimulate corneal epithelial wound healing in vitro and in vivo. We wished to identify which portion of the amino acid sequence of substance P might be responsible for this synergism. 2. Corneal epithelial migration was...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702550
更新日期：1999-05-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11707.x
更新日期：1988-11-01 00:00:00
abstract：BACKGROUND AND PURPOSE:11β-hydroxysteroid dehydrogenase type I (11β-HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic-pharmacodynamic (PK/PD) relationship of target inhibition after acute and repea...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13251
更新日期：2015-10-01 00:00:00
abstract：:1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 rece...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705929
更新日期：2004-11-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1975.tb07363.x
更新日期：1975-02-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703965
更新日期：2001-04-01 00:00:00
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pub_type： 杂志文章
doi：10.1111/j.1476-5381.1996.tb15690.x
更新日期：1996-09-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1996.tb15430.x
更新日期：1996-06-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1991.tb12290.x
更新日期：1991-04-01 00:00:00
abstract：:1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376...
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pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb14775.x
更新日期：1994-02-01 00:00:00
abstract：:Myoclonus induced by catechol in the guinea-pig is not altered by manipulation of cerebral 5-hydroxytryptamine (5-HT). The administration of catechol does not alter brain levels of 5-HT or its metabolite 5-hydroxyindole acetic acid. This form of myoclonus therefore is not of relevance to the 5-HT-sensitive post-anoxic...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1979.tb10837.x
更新日期：1979-07-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705650
更新日期：2004-05-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1981.tb10453.x
更新日期：1981-06-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2009.00324.x
更新日期：2009-09-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1987.tb11281.x
更新日期：1987-08-01 00:00:00
abstract：:1. The release of prostaglandin D2 (PGD2) during immediate allergic reactions in human skin was investigated in vivo and in vitro. 2. Skin exudates were collected from abraded sites on the thigh of atopic subjects sensitive to D. pteronyssinus antigen and from non-atopic control subjects. Challenge with antigen caused...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11588.x
更新日期：1988-07-01 00:00:00
