Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Chem Biol Drug Des. 2018 May;91(5):996-1006. doi: 10.1111/cbdd.13166. Epub 2018 Jan 24.
Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed.
血管破坏剂（VDAs）是一组癌症治疗药物，可导致已建立的肿瘤血管特异性且不可逆转的破坏，并完全阻断肿瘤中的血流。DMXAA（ASA404）或 Vadimezan，一种基于黄酮乙酸的药物，是最有前途的 VDAs，可导致肿瘤中的血流迅速关闭，但不会在正常组织中关闭。血管破坏的确切机制尚不清楚；然而，DMXAA 的作用机制包括（i）诱导内皮细胞凋亡；（ii）肿瘤出血性坏死和缺血；（iii）血清素（5-HT）释放；（vi）刺激固有免疫系统；（v）产生炎症细胞因子，例如 TNF、IL-6、GCSF、KC、IP-10 和 MCP-1；（vi）激活 NFκB 和 p38（MAPK）；（vii）产生一氧化氮；和（viii）降低肿瘤能量和膜周转率。尽管临床前和 I/II 期研究取得了显著成果，但 DMXAA 在 III 期临床试验中失败。造成这种惊人差异的原因之一是小鼠和人类之间的 STING 受体变异。在这篇综述中，将讨论 DMXAA 的开发、作用机制、临床试验、联合治疗以及该药物的未来。
