Stereochemistry | ACHIRAL |
Molecular Formula | C17H13O4.Na |
Molecular Weight | 304.2725 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[Na+].CC1=CC=C2C(=O)C3=C(OC2=C1C)C(CC([O-])=O)=CC=C3
InChI
InChIKey=CUHSZPRXKQDLCJ-UHFFFAOYSA-M
InChI=1S/C17H14O4.Na/c1-9-6-7-13-15(20)12-5-3-4-11(8-14(18)19)17(12)21-16(13)10(9)2;/h3-7H,8H2,1-2H3,(H,18,19);/q;+1/p-1
Vadimezan (5,6-dimethyl(xanthenone-4-acetic acid), ASA404, DMXAA) is a fused tricyclic analogue of flavone acetic acid with potential antineoplastic activity. In pre-clinical mouse tumour models it was demonstrated that administration of Vadimezan rapidly leads to disruption of the existing vasculature in the tumour and consequent haemorrhagic necrosis of the tumour. This was consistent with the finding that a single dose of Vadimezan induced a prolonged reduction in the growth of xenografted tumours in animal models. The ability to disrupt the vasculature in these pre-clinical models has been attributed to a rapid induction of cytokines, particularly TNFα (tumour necrosis factor α), serotonin and nitric oxide, resulting in hemorrhagic necrosis and a decrease in angiogenesis. Despite the fact that the molecular targets for the drug remained unknown, the promising pre-clinical results led to Vadimezan being selected for clinical development. Results of Phase I trials showed some restriction of tumour blood flow within 24 h of treatment, although this was not as dramatic as seen in pre-clinical models. Unlike the animal models, there was also very little evidence for the rapid death of blood vessels or for increases in TNFα levels in human tumors. No difference in antitumour activity, cytokine induction or toxicity was observed between two parallel Phase I trials, one dosed weekly and the other dosed every 3 weeks. Therefore the drug proceeded to Phase II clinical trials, dosed every 21 days in combination with chemotherapeutic agents. These trials indicated the drug had small benefits in the treatment of non-small-cell lung cancer and prostate cancer. However, a subsequent Phase III clinical trial was not able to reproduce this response and clinical development was halted.
Originator
Approval Year
Doses
AEs
Sourcing
PubMed
Patents
Sample Use Guides
1800 mg/m2 i.v. following the administration of paclitaxel and carboplatin on day 1 of each 3-week cycle
Route of Administration:
Intravenous
HUVECs (4x10^5 cells/well) were subcultured into sixwell plates pre-coated with 1% gelatin (Sigma) and allowed to grow to approximately 80% confluence before starvation for 16 h in medium 200/0.5%FBS (fetal bovine serum).HUVECs were then pre-incubated for 1 h with medium 200/0.1% FBS in the presence/absence of inhibitors (Vadimezan 100 μM) at the stated concentrations, before stimulation for 10 min with 50 ng/ml human VEGF165 (Symansis). Cells were lysed and the lysates were analysed by Western blotting using antibodies against phosphorylated ERK (extracellular-signal-regulated kinase) 1/2 (Thr202/Tyr204) or phosphorylated VEGFR2 (Tyr951) (Cell Signalling Technology).