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.
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Research Article|
January 20 2012
DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular
Christina M. Buchanan;
Christina M. Buchanan
*Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
†Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Jen-Hsing Shih;
Jen-Hsing Shih
*Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
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Jonathan W. Astin;
Jonathan W. Astin
*Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
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Gordon W. Rewcastle;
Gordon W. Rewcastle
†Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
‡Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
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Jack U. Flanagan;
Jack U. Flanagan
†Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
‡Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
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Philip S. Crosier;
Philip S. Crosier
*Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
†Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Peter R. Shepherd
*Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
†Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Correspondence: Professor Peter R. Shepherd (email [email protected]).
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Publisher: Portland Press Ltd
Received:
August 16 2011
Revision Received:
November 04 2011
Accepted:
December 05 2011
Accepted Manuscript online:
December 05 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 122 (10): 449–465.
Article history
Received:
August 16 2011
Revision Received:
November 04 2011
Accepted:
December 05 2011
Accepted Manuscript online:
December 05 2011
Citation
Christina M. Buchanan, Jen-Hsing Shih, Jonathan W. Astin, Gordon W. Rewcastle, Jack U. Flanagan, Philip S. Crosier, Peter R. Shepherd; DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular. Clin Sci (Lond) 1 May 2012; 122 (10): 449–465. doi: https://doi.org/10.1042/CS20110412
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