WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 201050
Description: Vadimezan, also known as DMXAA and ASA404, is a fused tricyclic analogue of flavone acetic acid with potential antineoplastic activity. Vadimezan induces the cytokines tumor necrosis alpha (TNF-alpha), serotonin and nitric oxide, resulting in hemorrhagic necrosis and a decrease in angiogenesis. This agent also stimulates the anti-tumor activity of tumor-associated macrophages.
MedKoo Cat#: 201050
Name: Vadimezan (DMXAA)
Chemical Formula: C17H14O4
Exact Mass: 282.08921
Molecular Weight: 282.29
Elemental Analysis: C, 72.33; H, 5.00; O, 22.67.
Synonym: ASA404; ASA 404; ASA404; AS1404; AS 1404; AS1404; DMXAA; Vadimezan
IUPAC/Chemical Name: (5,6-Dimethyl-9-oxo-9H-xanthen-4-yl)-acetic acid
InChi Key: XGOYIMQSIKSOBS-UHFFFAOYSA-N
InChi Code: InChI=1S/C17H14O4/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)
SMILES Code: O=C(O)CC1=CC=CC(C2=O)=C1OC3=C2C=CC(C)=C3C
Appearance: Light brown to brown solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||Vadimezan (ASA404, NSC 640488, DMXAA) is a vascular disrupting agents (VDA) and competitive inhibitor of DT-diaphorase with Ki of 20 μM and IC50 of 62.5 μM in cell-free assays, respectively.|
|In vitro activity:||In murine macrophages, DMXAA had a minimal effect on NF-κB activation. In comparison, LPS elicited significantly higher levels of NF-κB-dependent proinflammatory cytokines, e.g., TNF-α and IL-1β, which correlated with rapid degradation of IκBα and increased nuclear NF-κB translocation. Furthermore, under conditions in which LPS strongly activated MAPKs within 15 min, DMXAA had no measurable effect over a 2-h time course. Recently, we have found that IFN-β mRNA is similarly up-regulated by DMXAA in primary human monocytes (data not shown). Reference: J Leukoc Biol. 2011 Mar;89(3):351-7. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21084628/|
|In vivo activity:||344SQ-ELuc NSCLC subcutaneous tumors respond dramatically to DMXAA, with a marked (∼2-logs) decrease in bioluminescence (BLI) signals post-drug injection (Figure 2A–B). This was accompanied by vascular thrombosis and hemorrhage in the tumor periphery, and by the development of extensive central necrosis (Figure 2C). The drop in BLI following DMXAA treatment was not due to direct tumor cell toxicity since DMXAA had no detrimental effect on 344SQ-ELuc cell viability (Figure S3). Instead, tumor BLI signal loss was attributable to greatly diminished blood, and hence luciferin substrate, perfusion which would diminish ATP-dependent light production. While decreased perfusion could conceivably have resulted from reversible vasoconstriction, given the massive tumor necrosis observed, it was more likely that decreased light emission was the result of tumor vessel thrombosis and rupture. RNA transcripts from spleens of mice treated in vivo with DMXAA also demonstrated induction of iNOS and down-regulation of Arg-1 (Figure 4A), as well as diminished anti-Arg-1 immunohistochemical staining (Figure 4B). Importantly, subcutaneous tumor lysates also demonstrated evidence of DMXAA-mediated repolarization (Figure 4C), with diminished Arg-1 staining being evident as early as 6 hours post-DMXAA exposure (Figure 4D). In summary, these results suggest that STING activation can mediate M2-like TAM re-education. Reference: PLoS One. 2014 Jun 18;9(6):e99988. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24940883/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 282.29 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Shirey KA, Nhu QM, Yim KC, Roberts ZJ, Teijaro JR, Farber DL, Blanco JC, Vogel SN. The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo. J Leukoc Biol. 2011 Mar;89(3):351-7. doi: 10.1189/jlb.0410216. Epub 2010 Nov 17. PMID: 21084628; PMCID: PMC3040469. 2. Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014 Jun 18;9(6):e99988. doi: 10.1371/journal.pone.0099988. PMID: 24940883; PMCID: PMC4062468.|
|In vivo protocol:||1. Shirey KA, Nhu QM, Yim KC, Roberts ZJ, Teijaro JR, Farber DL, Blanco JC, Vogel SN. The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo. J Leukoc Biol. 2011 Mar;89(3):351-7. doi: 10.1189/jlb.0410216. Epub 2010 Nov 17. PMID: 21084628; PMCID: PMC3040469. 2. Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014 Jun 18;9(6):e99988. doi: 10.1371/journal.pone.0099988. PMID: 24940883; PMCID: PMC4062468.|
1: Lou YC, Kao YF, Chin KH, Chen JK, Tu JL, Chen C, Chou SH. Backbone resonance assignments of the 54 kDa dimeric C-terminal domain of murine STING in complex with DMXAA. Biomol NMR Assign. 2014 Dec 9. [Epub ahead of print] PubMed PMID: 25487675.
2: Gao P, Zillinger T, Wang W, Ascano M, Dai P, Hartmann G, Tuschl T, Deng L, Barchet W, Patel DJ. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Cell Rep. 2014 Sep 25;8(6):1668-76. doi: 10.1016/j.celrep.2014.08.010. Epub 2014 Sep 4. PubMed PMID: 25199835.
3: Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014 Jun 18;9(6):e99988. doi: 10.1371/journal.pone.0099988. eCollection 2014. PubMed PMID: 24940883; PubMed Central PMCID: PMC4062468.
4: Yung R, Seyfoddin V, Guise C, Tijono S, McGregor A, Connor B, Ching LM. Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), in the brain and plasma. Cancer Chemother Pharmacol. 2014 Mar;73(3):639-49. doi: 10.1007/s00280-014-2395-y. Epub 2014 Jan 30. PubMed PMID: 24477604.
5: Gao P, Ascano M, Zillinger T, Wang W, Dai P, Serganov AA, Gaffney BL, Shuman S, Jones RA, Deng L, Hartmann G, Barchet W, Tuschl T, Patel DJ. Structure-function analysis of STING activation by c[G(2',5')pA(3',5')p] and targeting by antiviral DMXAA. Cell. 2013 Aug 15;154(4):748-62. doi: 10.1016/j.cell.2013.07.023. Epub 2013 Aug 1. PubMed PMID: 23910378.
6: Tang CK, Aoshi T, Jounai N, Ito J, Ohata K, Kobiyama K, Dessailly BH, Kuroda E, Akira S, Mizuguchi K, Coban C, Ishii KJ. The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant. PLoS One. 2013;8(3):e60038. doi: 10.1371/journal.pone.0060038. Epub 2013 Mar 21. PubMed PMID: 23555875; PubMed Central PMCID: PMC3605442.
7: Tijono SM, Guo K, Henare K, Palmer BD, Wang LC, Albelda SM, Ching LM. Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Br J Cancer. 2013 Apr 2;108(6):1306-15. doi: 10.1038/bjc.2013.101. Epub 2013 Mar 12. PubMed PMID: 23481185; PubMed Central PMCID: PMC3619269.
8: Yeniceli D, Deng X, Adams E, Dogrukol-Ak D, Van Schepdael A. Development of a CD-MEKC method for investigating the metabolism of tamoxifen by flavin-containing monooxygenases and the inhibitory effects of methimazole, nicotine and DMXAA. Electrophoresis. 2013 Feb;34(3):463-70. doi: 10.1002/elps.201200356. Epub 2012 Dec 26. PubMed PMID: 23161341.
9: Prantner D, Perkins DJ, Lai W, Williams MS, Sharma S, Fitzgerald KA, Vogel SN. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J Biol Chem. 2012 Nov 16;287(47):39776-88. doi: 10.1074/jbc.M112.382986. Epub 2012 Oct 1. PubMed PMID: 23027866; PubMed Central PMCID: PMC3501038.
10: Henare K, Wang L, Wang LC, Thomsen L, Tijono S, Chen CJ, Winkler S, Dunbar PR, Print C, Ching LM. Dissection of stromal and cancer cell-derived signals in melanoma xenografts before and after treatment with DMXAA. Br J Cancer. 2012 Mar 13;106(6):1134-47. doi: 10.1038/bjc.2012.63. PubMed PMID: 22415295; PubMed Central PMCID: PMC3304430.
11: McKeage MJ, Jameson MB; AS1404-201 Study Group Investigators. Comparative outcomes of squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of ASA404 (DMXAA) - retrospective analysis of pooled data. J Thorac Dis. 2010 Dec;2(4):199-204. doi: 10.3978/j.issn.2072-1439.2010.02.04.1. PubMed PMID: 22263047; PubMed Central PMCID: PMC3256477.
12: Buchanan CM, Shih JH, Astin JW, Rewcastle GW, Flanagan JU, Crosier PS, Shepherd PR. DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular. Clin Sci (Lond). 2012 May 1;122(10):449-57. doi: 10.1042/CS20110412. PubMed PMID: 22142330.
13: Jameson MB, Head M. Pharmacokinetic evaluation of vadimezan (ASA404, 5,6-dimethylxanthenone-4-acetic acid, DMXAA). Expert Opin Drug Metab Toxicol. 2011 Oct;7(10):1315-26. doi: 10.1517/17425255.2011.614389. Epub 2011 Aug 26. Review. PubMed PMID: 21870897.
14: Marysael T, Ni Y, Lerut E, de Witte P. Influence of the vascular damaging agents DMXAA and ZD6126 on hypericin distribution and accumulation in RIF-1 tumors. J Cancer Res Clin Oncol. 2011 Nov;137(11):1619-27. doi: 10.1007/s00432-011-1032-y. Epub 2011 Aug 21. PubMed PMID: 21858709.
15: Sun J, Wang LC, Fridlender ZG, Kapoor V, Cheng G, Ching LM, Albelda SM. Activation of mitogen-activated protein kinases by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) plays an important role in macrophage stimulation. Biochem Pharmacol. 2011 Nov 1;82(9):1175-85. doi: 10.1016/j.bcp.2011.07.086. Epub 2011 Jul 26. PubMed PMID: 21819972; PubMed Central PMCID: PMC3191304.
16: Peng S, Monie A, Pang X, Hung CF, Wu TC. Vascular disrupting agent DMXAA enhances the antitumor effects generated by therapeutic HPV DNA vaccines. J Biomed Sci. 2011 Mar 8;18:21. doi: 10.1186/1423-0127-18-21. PubMed PMID: 21385449; PubMed Central PMCID: PMC3062584.
17: Shirey KA, Nhu QM, Yim KC, Roberts ZJ, Teijaro JR, Farber DL, Blanco JC, Vogel SN. The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo. J Leukoc Biol. 2011 Mar;89(3):351-7. doi: 10.1189/jlb.0410216. Epub 2010 Nov 17. PubMed PMID: 21084628; PubMed Central PMCID: PMC3040469.
18: Baguley BC, Siemann DW. Temporal aspects of the action of ASA404 (vadimezan; DMXAA). Expert Opin Investig Drugs. 2010 Nov;19(11):1413-25. doi: 10.1517/13543784.2010.529128. Review. PubMed PMID: 20964495; PubMed Central PMCID: PMC3583340.
19: Brauer R, Wang LC, Woon ST, Bridewell DJ, Henare K, Malinger D, Palmer BD, Vogel SN, Kieda C, Tijono SM, Ching LM. Labeling of oxidizable proteins with a photoactivatable analog of the antitumor agent DMXAA: evidence for redox signaling in its mode of action. Neoplasia. 2010 Sep;12(9):755-65. PubMed PMID: 20824052; PubMed Central PMCID: PMC2933696.
20: Head M, Jameson MB. The development of the tumor vascular-disrupting agent ASA404 (vadimezan, DMXAA): current status and future opportunities. Expert Opin Investig Drugs. 2010 Feb;19(2):295-304. doi: 10.1517/13543780903540214. PubMed PMID: 20050824.
Vadimezan or ASA404 (originally DMXAA) is a tumor-vascular disrupting agent (tumor-VDA) that attacks the blood supply of a cancerous tumor to cause tumor regression. ASA404 was discovered by Bruce Baguley and William Denny and their teams at the Auckland Cancer Society Research Centre at the University of Auckland in New Zealand. It was licensed to Antisoma in 2001. Novartis acquired the worldwide rights for it in 2007 and it is being developed by Antisoma and Novartis. See wikipedia.
Novartis announced today (November 11, 2010) that the clinical trial program for the investigational cancer treatment ASA404 (vadimezan) will be discontinued and resources will be reallocated to other compounds in the oncology pipeline. The decision was made after interim results from a Phase III trial showed that ASA404 would not likely meet the primary endpoint of significantly extending overall survival when used in combination with chemotherapy for the second-line treatment of patients with advanced non-small cell lung cancer (NSCLC). (source: http://www.novartis.com/newsroom/media-releases/en/2010/1461276.shtml).