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An Overview on Vadimezan (DMXAA): the Vascular Disrupting Agent

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An Overview on Vadimezan (DMXAA): the Vascular Disrupting Agent See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/322146064 An overview on Vadimezan (DMXAA): The vascular disrupting agent Article in Chemical Biology & Drug Design · December 2017 DOI: 10.1111/cbdd.13166 CITATIONS READS 4 66 5 authors, including: Amir Daei Rana Jahanban-Esfahlan Tabriz University of Medical Sciences Tabriz University of Medical Sciences 6 PUBLICATIONS 10 CITATIONS 42 PUBLICATIONS 456 CITATIONS SEE PROFILE SEE PROFILE Khaled Seidi N Zarghami Tabriz University of Medical Sciences Tabriz University of Medical Sciences 21 PUBLICATIONS 123 CITATIONS 270 PUBLICATIONS 3,731 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: The comparison between the effects of pure curcumin and curcumin-loaded PLGA-PEG nanoparticle on telomerase and TRF1 genes expression in lung cancer cell line View project 3-D printing system to produce my model skin tissue View project All content following this page was uploaded by Amir Daei on 30 January 2018. The user has requested enhancement of the downloaded file. Received: 5 August 2017 | Revised: 29 November 2017 | Accepted: 17 December 2017 DOI: 10.1111/cbdd.13166 REVIEW An overview on Vadimezan (DMXAA): The vascular disrupting agent Amir Daei Farshchi Adli1 | Rana Jahanban-Esfahlan1,2 | Khaled Seidi1 | Sonia Samandari-Rad3,4 | Nosratollah Zarghami1,5,6 1Department of Medical Biotechnology, Faculty of Advanced Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific Medical Sciences, Tabriz University of and irreversible destruction of established tumor vessels, and the complete halt of Medical Sciences, Tabriz, Iran blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone- acetic acid- 2 Student Research Committee, Tabriz based drug, is the most promising VDAs that induces a rapid shutdown of blood flow University of Medical Sciences, Tabriz, Iran in tumors but not in normal tissue. The exact mechanism of vascular disruption is 3Faculty of Medicine, Physiology Research Center, Tehran University of Medical unknown; however, proposed direct and indirect mechanisms of action for DMXAA Sciences, Tehran, Iran comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and 4 Department of Physiology, Faculty of ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate im- Medicine, Tehran University of Medical mune system; (v) production of inflammatory cytokines, for example TNF, IL- 6, Sciences, Tehran, Iran 5Department of Clinical Biochemistry GCSF, KC, IP- 10, and MCP- 1; (vi) activation of NFκB and p38 (MAPK); (vii) pro- and Laboratory Medicine, Faculty of duction of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Medicine, Tabriz University of Medical Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in Sciences, Tabriz, Iran phase III clinical trials. The reason for this surprising discrepancy, among others, 6Iranian National Science Foundation, Tehran, Iran 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 Correspondence combination therapy, and the future of this drug will be discussed. Nosratollah Zarghami, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. KEYWORDS Email: [email protected] ASA404, cancer combination therapy, DMXAA, Vadimezan, vascular disrupting agents (VDAs) [7] 1 | INTRODUCTION antivascular agents. Small antivascular agents also include tubulin binding agents—for example, combretastatin- A4 phos- Cancer is a public health issue and one of the chief causes of phate,[8] OXi4503,[9] and flavonoid derivatives.[10] DMXAA death in the world with about 8.2 million deaths in 2012.[1,2] (5,6- dimethylxanthenone- 4- acetic acid, Vadimezan) is a flavo- The rate of cancer is expected to increase. So finding a new noid derivative that is considered one of the most promising effective remedy is a necessity. In recent years, targeting of antivascular agents.[11] Currently, DMXAA has undergone tumor vessels has been one of the main strategies for cancer several clinical trials. In this review, development, and mech- treatment, due to its unmatched characteristics.[3,4] Solid tu- anism of DMXAA action, the clinical trials, the combination mors require new blood vessels to deliver nutrients and oxy- therapy, and the forthcoming of this drug will be discussed. gen to the cancer cells to grow and survive.[5] As angiogenesis inhibitors interfere with the formation of new blood vessels in solid tumors, antivascular agents target the established vessels 1.1 | DMXAA development in the tumor tissue exclusively.[6] There are two main catego- The production of DMXAA drug was based on the discovery ries of antivascular agents: ligand-dependent agents and small that flavone- 8- acetic acid (FAA) can cause tumor necrosis Chem Biol Drug Des. 2018;1–12. wileyonlinelibrary.com/journal/cbdd © 2017 John Wiley & Sons A/S | 1 2 | DAEI FARSHCHI ADLI ET AL. (Figure 1). The FAA, a flavonoid group—which was initially (DMXAA direct mechanism of action) includes specific synthesized as a non- steroidal anti- inflammatory drug—sur- and irreversible destruction of established tumor vascula- prisingly, demonstrated antitumor properties, as well.[12–14] tures and the complete blockade of tumor blood flow.[14,20] However, the FAA was unsuccessful in clinical trials.[15] This effect is due to the induction of apoptosis in tumor Therefore, the researchers at the Auckland Cancer Society endothelial cells, which, in turn, causes hemorrhagic ne- Research Center (ACSRC) began testing for a more active crosis and ischemia in tumor tissues.[20–22] The destruction form of the FAA and were able to synthesize DMXAA, a de- of tumor vessels can be considered as the first impact of rivative of xanthone and FAA analog. DMXAA has 10 to 15 DMXAA that appears about 30 min after injection.[23,24] times more activity than FAA. The other names of this drug The destruction of tumor vessel through aggregation of are ASA404 and Vadimezan.[16] platelets stimulates and increases the release of serotonin (5- HT) in the plasma.[23,24] Thus, we can consider the sta- ble form of serum serotonin (5HIAA) as an antivascular 1.2 | Proposed mechanism of marker.[25] The activation of the innate immune system action of DMXAA is an indirect effect of DMXAA, a feature which is con- The structure of tumor vascularization is different from nor- sidered to be absent in other antivascular agents.[26] The mal tissues of the body.[17] Tumor vessels are immature be- induction of innate immune system stimulates inflamma- cause their hierarchical network build up is unlike normal tory cytokine production which is responsible for tumor- vascular tissues, in fact, they are unevenly distributed and specific inflammatory responses.[11,27] Approximately, chaotic.[5] Tumor endothelial cells are structurally and physi- 4 hr after injection of DMXAA, the amount of interleukin ologically abnormal, and more permeable to macromolecules 6 (IL- 6), tumor necrosis factor (TNF), granulocyte colony compared to normal tissues, and also their blood flow rate is stimulating factor (GCSF), and several chemokines—such far less than normal tissues.[18] These features are considered as macrophage inflammatory protein 1α (MIP-1α), IP- to be the major weaknesses of tumor vessels and, therefore, 10 and, KC—increases.[28–30] The rate of cytokine rising can be utilized as points of a target for eliminating tumors.[19] caused by DMXAA is greater in tumor tissues compared Two types of mechanisms of action have been proposed to plasma.[29] Although the molecular target of DMXAA for DMXAA: direct and indirect. DMXAA direct effect is yet unknown, it seems that, unlike the human stimu- lator of interferon gene (STING) that is not induced by DMXAA,[31] the induction of the innate immune system in mice occurs by STING. DMXAA stimulates pathways that have been observed in NFκB activation in mono- cytes,[30] vascular endothelial cells,[20] and various tumor cells.[32] NFκB also promotes the production of TNF and other inflammatory cytokines[33]—which change the or- ganization of the cytoskeleton in the tumor endothelial cells, thus, alerting their structure and shape.[34] DMXAA also escalates the levels of nitric oxide.[35] Both TNF and nitric oxide elicit vascular disrupting properties.[11] The production of TNF and nitric oxide along with other cyto- kines is the reason of tumor necrosis.[12] Three functions of increased permeability increased apoptosis, and de- creased blood flow is mediated by TNF because in mice lacking the TNF gene[36] or TNF receptor gene,[28] these three functions cannot be seen. The presence of TNF, how- ever, reduces the maximum tolerated dose of DMXAA. Consequently, TNF is an important factor affecting the performance and toxicity of DMXAA.[28] The other effects of DMXAA include activation of p38 (MAPK) and TBK1-IRF3 pathways,[37] and reduction of tumor energetics and membrane turnover.[38] Studies have, also, shown that DMXAA inhibits the activation of platelet and induces thrombosis through inhibition of phosphodies- [39] FIGURE 1 The chemical structure of DMXAA and related terase and thromboxane A2 signaling. Table 1 summa- compounds[12] rizes the proposed mechanisms for DMXAA. DAEI FARSHCHI ADLI ET AL. | 3 myelosuppression.[42,43] Significant clinical changes in vi- 1.3 Clinical efficacy | sion, retinal, and electrophysiological parameters were not The DMXAA drug can be utilized alone or in combination seen after six times injections of DMXAA.[44] The inves- with other anticancer agents to treat cancer. A web search tigation on the blood flow parameters made via a dynamic with the terms DMXAA, Vadimezan, and ASA404 in the contrast- enhanced MRI method on sixteen phase I patients database of clinical studies (https://clinicaltrials.gov) culmi- before and 6–24 hr after treatment with DMXAA showed nated in 18 results. These clinical trials are summarized in that DMXAA in doses of 500 to 4,900 had reduced the tumor Tables 2 and 3.
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