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.