DMXAA (Vadimezan, ASA404) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). DMXAA could enhance the immunogenicity of influenza split vaccine which led to significant increase in protective responses against live influenza virus challenge in mice compared to split vaccine alone. Using OVA as a model antigen, DMXAA was demonstrated to improve on the antigen specific immune responses and induce a preferential Th2 (Type-2) response. 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 in blood during clinical trials. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and approximately 750-fold increase in IFN-beta mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88-, Toll-interleukin 1 receptor domain-containing adaptor inducing IFN-beta-, IFN promoter-stimulator 1-, and inhibitor of kappaB kinase-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA is a VDA currently in advanced phase II clinical trials.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Drug Des Devel Ther (2015). Figure 6. DMXAA|
|Method||Cell cycle analysis|
|Cell Lines||A549 cells|
|Incubation Time||24 h|
|Results||Taken together, the results show that DMXAA can regulate the cell cycle distribution, contributing to its anticancer effect in A549 cells.|
DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular.
Buchanan CM, et al. Clin Sci (Lond). 2012 May 1;122(10):449-57. PMID: 22142330.
Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.
McKeage MJ, et al. Br J Cancer. 2008 Dec 16;99(12):2006-12. PMID: 19078952.
The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis.
Roberts ZJ, et al. J Exp Med. 2007 Jul 9;204(7):1559-69. PMID: 17562815.
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Fruquintinib (HMPL-013) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 33, 0.35, and 35 nM, respectively.
SUN11602 is a novel aniline compound with basic fibroblast growth factor-like activity.
Anlotinib Dihydrochloride is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFRα/β, c-Kit, and Ret.
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