PUBLICATION
DMXAA (Vadimezan, ASA404) is a Multi-kinase Inhibitor Targetting VEGF-R2 in Particular
- Authors
- Buchanan, C.M., Shih, J.H., Astin, J.W., Rewcastle, G.W., Flanagan, J.U., Crosier, P.S., and Shepherd, P.R.
- ID
- ZDB-PUB-111207-1
- Date
- 2012
- Source
- Clinical science (London, England : 1979) 122(10): 449-457 (Journal)
- Registered Authors
- Crosier, Phil
- Keywords
- none
- MeSH Terms
-
- Xanthones/chemistry
- Xanthones/pharmacology*
- Humans
- Signal Transduction/drug effects
- Protein Kinase Inhibitors/pharmacology*
- Animals
- Models, Molecular
- Zebrafish/embryology
- Neovascularization, Physiologic/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/chemistry
- PubMed
- 22142330 Full text @ Clin. Sci. (Lond.)
Citation
Buchanan, C.M., Shih, J.H., Astin, J.W., Rewcastle, G.W., Flanagan, J.U., Crosier, P.S., and Shepherd, P.R. (2012) DMXAA (Vadimezan, ASA404) is a Multi-kinase Inhibitor Targetting VEGF-R2 in Particular. Clinical science (London, England : 1979). 122(10):449-457.
Abstract
The flavone acetic acid derivative 5,6-dimethylxanthenone-4-acetic acid (DMXAA, Vadimezan, ASA404) is a drug that displayed vascular disrupting activity and induced hemorrhagic necrosis and tumour regression in preclinical 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 none the less 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 preclinical findings and 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 find that at concentrations achieved in blood during clinical trials that DMXAA has inhibitory effects against several kinases, with most potent effects being on members of the VEGF receptor tyrosine kinase family. Some analogues of DMXAA were even more effective inhibitors of these kinases, in particular 2-Me-XAA and 6-Me-XAA. The inhibitory effects were greatest against VEGF-R2 and consistent with this we find that DMXAA, 2-Me-XAA and 6-Me-XAA were able to block angiogenesis in zebrafish embryos and also block VEGF-R2 signalling in human umbilical vein endothelial cells (HUVEC). These data together indicate that at least part of DMXAA?s effects are due to it acting as a multi-kinase inhibitor and that the anti-VEGF receptor activity in particular may contribute to the non-immune-mediated effects of DMXAA on vasculature.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping