DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGF-R2 in particular

Show simple item record Buchanan, Christina en Shih, Jen-Hsing en Rewcastle, Gordon en Astin, Jonathan en Flanagan, Jack en Crosier, Philip en Shepherd, Peter en 2012-01-25T02:07:29Z en 2012 en
dc.identifier.citation Clinical Science 122:449-457 2012 en
dc.identifier.issn 0143-5221 en
dc.identifier.uri en
dc.description.abstract The flavone acetic acid derivative DMXAA [5,6-dimethylXAA (xanthenone-4-acetic acid), Vadimezan, ASA404] is a drug that displayed vascular-disrupting activity and induced haemorrhagic necrosis and tumour regression in pre-clinical animal models. Both immune-mediated and non-immune-mediated effects contributed to the tumour regression. The vascular disruption was less in human tumours, with immune-mediated effects being less prominent, but nonetheless DMXAA showed promising effects in Phase II clinical trials in non-small-cell lung cancer. However, these effects were not replicated in Phase III clinical trials. It has been difficult to understand the differences between the pre-clinical findings and the later clinical trials as the molecular targets for the agent have never been clearly established. To investigate the mechanism of action, we sought to determine whether DMXAA might target protein kinases. We found that, at concentrations achieved in blood during clinical trials, DMXAA has inhibitory effects against several kinases, with most potent effects being on members of the VEGFR (vascular endothelial growth factor receptor) tyrosine kinase family. Some analogues of DMXAA were even more effective inhibitors of these kinases, in particular 2-MeXAA (2-methylXAA) and 6-MeXAA (6-methylXAA). The inhibitory effects were greatest against VEGFR2 and, consistent with this, we found that DMXAA, 2-MeXAA and 6-MeXAA were able to block angiogenesis in zebrafish embryos and also inhibit VEGFR2 signalling in HUVECs (human umbilical vein endothelial cells). Taken together, these results indicate that at least part of the effects of DMXAA are due to it acting as a multi-kinase inhibitor and that the anti-VEGFR activity in particular may contribute to the non-immune-mediated effects of DMXAA on the vasculature. en
dc.publisher Biochemical Society en
dc.relation.ispartofseries Clinical Science en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.title DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGF-R2 in particular en
dc.type Journal Article en
dc.identifier.doi 10.1042/CS20110412 en
pubs.begin-page 449 en
pubs.volume 122 en
dc.rights.holder Copyright: The Authors; Biochemical Society en
dc.identifier.pmid 22142330 en
pubs.end-page 457 en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 253013 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Molecular Medicine en Pharmacology en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2011-12-06 en
pubs.dimensions-id 22142330 en

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