生物活性

• 描述DMXAA is a competitive inhibitor of DT-diaphorase with an IC50 value of 62.5μM and a K_i value of 20μM. DMXAA blocked DT-diaphorase activity in DLD-1 cells with an IC50 value of 49.6μM. It led to approximate 25% inhibition of cytochrome b5 reductase, although the inhibition plateau was between 250μM and 2 mM^[1]. DMXAA also showed potent inhibitory effect on vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, as well as other protein kinases including homeodomain-interacting protein kinase 2, casein kinase 2, Haspin, Aurora kinases, PIM kinases, c-FMS, and tropomyosin-receptor kinases. The IC50 values of DMXAA against VEGFR1 and VEGFR2 were 119 and 11μM, respectively. DMXAA at 25μM showed partial anti-angiogenic effect in an embryonic zebrafish model. DMXAA at the concentration of 30μM significantly reduce the VEGF-induced activation of extracellular-signal-regulated kinase in human umbilical vein endothelial cells^[2]. In female Wistar rats, a single dose of DMXAA (300mg/kg, i.p.) significantly delayed the growth of NMU-induced primary mammary tumors as compared to vehicle-treated group^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HECPP cells	10 ug/mL	Function assay	-	Activation of NF-kappaB in HECPP cells at 10 ug/mL	17616114
  human BJ cells	-	Cytotoxic assay	24 h	Cytotoxicity against human BJ cells after 24 hrs by MTT assay, CC50=48.9 μM	24518295

• 动物研究
  剂量	Mice: 17.5 mg/kg, 20 mg/kg[3] (i.p.); 30 mg/kg[4] (p.o.) Rat: 100 mg/kg - 350 mg/kg[5] (i.p.)
  给药途径	i.p., p.o.
  动物药代数据	Animal Mice[4] Dose 30 mg/kg (p.o.) 25 mg/kg (i.p. or i.v.) Administration p.o. i.p. or i.v. Cmax 358 ± 25 μmol/l (p.o.) 570 ± 21 μmol/l (i.p.) 470 ± 12 μmol/l (i.v.) T1/2 9.2 h (p.o.) 2.7 h (i.p.) 3.3 h (i.v.) AUC 1392 μmol·h/l (p.o.) 1715 μmol·h/l (i.p.) 1595 μmol·h/l (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01031212	Tumors	Phase 1	Withdrawn(The investigator has... more >> left the institution (UCSF) prior to study start-up) Collapse <<	June 2013	United States, California ... more >> UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California, United States, 94115 Collapse <<
  NCT00662597	Non-Small Cell Lung Cancer	Phase 3	Terminated	-	-
  NCT01057342	Lung Cancer	Phase 2	Completed	-	Switzerland ... more >> Saint Claraspital AG Basel, Switzerland, CH-4016 Universitaetsspital-Basel Basel, Switzerland, CH-4031 Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni Bellinzona, Switzerland, CH-6500 Inselspital Bern Bern, Switzerland, CH-3010 Spitalzentrum Biel Biel, Switzerland, CH-2501 Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland, CH-1011 Kantonsspital Olten Olten, Switzerland, CH-4600 Onkologie Schaffhausen Schaffhausen, Switzerland, CH-8200 Kantonsspital - St. Gallen St. Gallen, Switzerland, CH-9007 Regionalspital Thun, Switzerland, 3600 Kantonsspital Winterthur Winterthur, Switzerland, CH-8400 Klinik Hirslanden Zurich, Switzerland, CH-8032 Collapse <<

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• 参考文献

• [1] Phillips RM. Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA): implications for bioreductive drug development. Biochem Pharmacol. 1999 Jul 15;58(2):303-10.

  [2] 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.

  [3] Liu JJ, Ching LM, Goldthorpe M, Sutherland R, Baguley BC, Kirker JA, McKeage MJ. Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours. Cancer Chemother Pharmacol. 2007 Apr;59(5):661-9.

  [4] Zhao L, Kestell P, et al. Oral activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice. Cancer Chemother Pharmacol. 2002 Jan;49(1):20-6.

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