DMXAA (Vadimezan) is a selective DT-diaphorase inhibitor with a Ki value of 20μM and an IC50 value of 62.5μM[1]. DMXAA (Vadimezan) is a tumor blood vessel disrupting agent (tumor-VDA) that induces rapid closure of blood flow in tumors to cause tumor regression[2]. DMXAA (Vadimezan) is an agonist of stimulator of interferon genes (STING) and a potent inducer of type I IFN and other cytokines[3]. DMXAA (Vadimezan) is also a multi-kinase inhibitor, specifically targeting VEGFR 2 [4].
In vitro, DMXAA (Vadimezan) (500 μg/mL) treated HECPP cells for 24 hours, inducing 50% cell apoptosis and up-regulating IP-10 mRNA levels [5]. DMXAA (Vadimezan) (0.1μM-10μM) induced G1 arrest in A549 cells in a dose-dependent manner, thereby inducing apoptosis and autophagy, and also increased beclin1 and microtubule-associated protein 1A/1B-light chain in the cells. 3 (LC 3-II) expression is enhanced [6].
In vivo, DMXAA (Vadimezan) (25 mg/kg; i.p.) significantly improved survival and reduced influenza-induced weight loss in C57BL/6J mice infected with H1N1 influenza virus, resulting in a survival rate of 60%, compared with control survival only 20%[7]. DMXAA(Vadimezan) (25mg/kg) administered to mice via intraperitoneal injection significantly reduced the bioluminescence (BLI) signal in subcutaneous tumor cells, and necrosis occurred around the tumor without bleeding [8].
References:
[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..[J] Biochem Pharmacol. 1999 Jul 15;58(2):303-10.
[2] Adli A D F , Jahanban-Esfahlan R , Seidi K , et al. An overview on Vadimezan (DMXAA): The vascular disrupting agent.[J]. Chem Biol Drug Des, 2018(5).
[3]Downey C M, Aghaei M, Schwendener R A, et al. 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[J]. PloS one, 2014, 9(6): e99988.
[4]Buchanan CM, Shih JH, Astin JW, et al. DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular.[J]Clin Sci (Lond). 2012 May 1;122(10):449-57.
[5]Ching L M, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5, 6-dimethylxanthenone-4-acetic acid[J]. British journal of cancer, 2002, 86(12): 1937-1942.
[6]Zhou S F , Pan S T,et al.Proteomic response to 5,6-dimethylxanthenone 4-acetic acid (DMXAA, vadimezan) in human non-small cell lung cancer A549 cells determined by the stable-isotope labeling by amino acids in cell culture (SILAC) approach[J].Drug Design Development & Therapy, 2015.
[7]Shirey K A , Nhu Q M , Yim K C , et al. The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo.[J].Journal of Leukocyte Biology, 2011, 89.
[8] Downey C M , Mehrnoosh A , Schwendener R A ,et al.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[J].PLoS ONE, 2014, 9(6):e99988-.
DMXAA (Vadimezan)是一种选择性的DT-心肌黄酶抑制剂，Ki值为20μM，IC50值为62.5μM[1]。DMXAA (Vadimezan)是一种肿瘤血管破坏剂（肿瘤-VDA），可诱导肿瘤中的血流快速关闭以引起肿瘤消退[2]。DMXAA (Vadimezan)是干扰素基因刺激因子（STING）的激动剂，也是I型IFN和其他细胞因子的有效诱导剂[3]。DMXAA (Vadimezan)也是一种多激酶抑制剂，特别是靶向VEGFR 2[4]。
在体外，DMXAA (Vadimezan)（500 μg/mL）处理HECPP细胞24h，诱导了50% 细胞凋亡，上调了IP-10的mRNA水平[5]。DMXAA (Vadimezan)（0.1μM-10μM）以剂量依赖性方式诱导了A549细胞G1期阻滞，从而诱导细胞凋亡和自噬，还使细胞中的beclin1和微管相关蛋白1A/1B-轻链3（LC 3-II）的表达增强[6]。
在体内，DMXAA (Vadimezan) (25 mg/kg; i.p.)显著提高了感染H1N1流感病毒的C57BL/6J小鼠存活率，减少流感引起的体重减轻，使存活率达60%, 而对照组存活率仅为20%[7]。DMXAA (Vadimezan) (25 mg/kg)通过腹腔注射给予小鼠，显著降低了皮下肿瘤细胞中生物发光（BLI）信号，肿瘤周边发生坏死且不存在出血[8]。