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

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An overview on Vadimezan (DMXAA): The vascular disrupting agent

Article in Chemical Biology & Drug Design · December 2017 DOI: 10.1111/cbdd.13166

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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 stable 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 cytokines is the reason of tumor necrosis.[12] Three functions of increased permeability increased apoptosis, and decreased 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, however, 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. Our main focus in this study is on present- blood flow.[45] ing the newer information, including clinical trials, that, to Following the above studies, an additional but complete the best of our knowledge, have not been discussed in detail double-blinded, randomized, crossover study on new fif- [11,12,40,41] earlier, in previous review articles. Furthermore, teen patients inflicted by refractory tumors was carried out, for the completeness purposes, we have also included a brief using weekly sequential doses of 300 to 3,000, to closely summary of the clinical trials that have already been dis- compare the impact of these sequential doses on the immu- cussed in detail in previous review articles to help refer the nity, cardiac, and visual disturbances seen in these new fif- interested readers to the relevant sources. teen patients with those seen in the former patients in prior studies. A dose-dependent increase in the plasma 5-HIAA level was detected, which essentially proves that the dam- 1.4 Phase I clinical trials of ASA404: | age of blood vessels leads to the serotonin release. At high single agent 2 doses of 2,400/3,000 mg/m , a transient and moderate in- So far, the data for four single-agent ASA404 phase I clinical crease in QTc was noted. The results showed that the dose of trials have been published. The first three clinical trials have 1,200–1,800 had the least significant side-effect on the QTc [40] been well reviewed by Baguley and McKeage in 2010. interval and had the highest therapeutic effect with blood ves- Here, we will just summarize them. In the first study, forty- sel destruction, which was shown by the HIAA biomarker six patients with cancer participated in a dose-escalation concentration.[46] (phase I study) sponsored by UK cancer research. A partial The fourth study was sponsored by Novartis response in a locally recurrent melanoma patient in the dose Pharmaceuticals, a Single Center, open-label study for the 2 [42] of 1,300 mg/m was observed. characterization of parameters—such as absorption, dis- In a parallel study sponsored by UK cancer research, tribution, metabolism, and excretion—with a single dose sixty-three patients with cancer once every 3 weeks received of 3,000 mg/m2 DMXAA [14C] in seven patients with the 2 6 to 4,900 mg/m DMXAA injections in 20 min. Similar to advanced tumor. In this study, the drug’s mass balance was the aforementioned study, in this study, partial response with 86.9% in both urine and feces. The study also discovered two 2 the dose of 1,100 mg/m in a squamous cell carcinoma pa- new metabolites of M7 and M10 in the pathway for the me- [43] tients was also observed. tabolism of this drug.[47] In conclusion, the application of DMXAA at low doses was well tolerated by the patients with cancer in the above studies and the low doses of DMXAA did not cause 1.5 | Phase I clinical trials of ASA404: combination therapy The data from phase I and ex vivo studies suggest that TABLE 1 Proposed mechanisms of action for DMXAA DMXAA may have a better performance in combination Direct mechanisms with the other anticancer drugs. Animal model studies have Specific and irreversible destruction of tumor vessels shown that DMXAA acts as synergistic chemotherapy.[48–50] Decreasing tumor blood flow There are seven records for phase I clinical trials of combina- Apoptosis of endothelial cells tion therapy on the website of clinical trials. One study has Hemorrhagic necrosis and ischemia in tumor been withdrawn, and four studies have no reports. Two phase Release of serotonin (5-HT) I studies were also conducted by Novartis Pharma in Japan, Indirect mechanisms which has published papers and is briefly discussed here. Induction of innate immune system The first trial was performed on fifteen Japanese patients with NSCLC. Of these fifteen patients, three received Production of inflammatory cytokines including TNF, IL-6, 2 2 GCSF KC, IP-10, and MCP-1 600 mg/m doses, six received 1,200 mg/m , and the re- maining six received a dose of 1,800 mg/m2 DMXAA plus NFκB and p38 (MAPK) activation 200 mg/m2 carboplatin and paclitaxel (AUC = 6) at six times Production of nitric oxide in 21 days. In this single-arm, open-label trial, Vadimezan Reducing tumor energetics and membrane turnover and paclitaxel/carboplatin were used in first treatment line. 4 | DAEI FARSHCHI ADLI et al. [39] [40,41,57] [41,43] [44] a NCT01299701 NCT00856336 NCT01278849 NCT00863733 NCT00003697 NCT number (ref) Completed Completed Terminated Completed Completed Status corrected cardiac QT 2 rate- interval; Visual disturbances and, visual disturbance at the highest dose level 4,900 mg/ m urinary incontinence Moderate increases in the heart — Not reported Anxiety, urinary incontinence, Anxiety, visual disturbance, and Main adverse effects ; ASA404 2 ; ASA404 is well 2 ; one unconfirmed 2 2 were 1,200–1,800; increase in plasma 5- HIAA was dose- dependent mass balance was 86.9% in urine and feces were 1,200–1,800 mg/m partial response at 1,300 mg/m tolerated; one partial response at 1,300 mg/m is well tolerated Recommended doses for phase II studies Two novel metabolites were identified; Not reported Recommended doses for phase II trials MTD was 3,700 mg/m Results ) 2 6–4,900 6–4,900 300–3,000 900–1,800 3,000 mg [14C] labeled Dosage (mg/m 15 7 5 63 49 Enrollment tumors cancers with Hepatic impair - ment General Refractory Advanced Cancer General Setting I I I I I Phase Summary of ASA404 phase I single agent every 3 weeks crossover, once a week open- label, single dose single dose once a week Study Single agent, Single agent Single- agent Single agent, Single agent, No paper is published. TABLE 2 MTD, maximum tolerated dose. a DAEI FARSHCHI ADLI et al. | 5 [48] [49] [50–52] [53] [54] (Continues) NCT00832494 NCT01285453 NCT00111618 NCT01057342 NCT00674102 NCT01031212 NCT01240642 NCT01278758 NCT01290380 NCT01299415 NCT number (ref) Completed Completed Completed Completed Completed Withdrawn Terminated Terminated Terminated Terminated Status pain, nausea, vomiting, and anemia fatigue, neutropenia, decreased appetite, constipation, and injection site pain of cardiac adverse events and neutropenia in Combination group toxicities occurred pain, peripheral neuropathy neutropenia, and alopecia Not reported Infusion site Not reported Not reported Not reported Alopecia, Not reported Higher incidence No unexpected Injection site Main adverse effect HIAA combining ASA404 with a standard chemotherapy in five patients (55%); ASA404 had an acceptable tolerability in combination with docetaxel CRMPC enrollments disease in seven patients (47%); a dose- dependent increase in plasma 5- This study established the feasibility of Not reported Not reported Not reported Not reported Partial response in one patients; stable disease Not reported Combination had acceptable toxicity; activity in The trial was prematurely closed after 17 Partial response in four patients (27%); stable Results ) 2 600–1,800 — 1,200–1,800 1,200–1,800 Not reported Dosage (mg/m 800 Not reported 1,200 1,800 600–1,800 76 + 30 — 27 7 54 Enrollment 9 17 74 17 15 solid tumors cancer cancer recurrent solid tumors in Japanese patients prostate cancer Japanese patients NSCLC Refractory Metastatic Metastatic Solid tumor Setting Advanced or Solid tumors Metastatic ES- SCLC NSCLC I- II I I I I Phase I I II II I Summary of ASA404 combination therapy 3 weeks paclitaxel/cetuximab taxel + carboplatin chemotherapy apy 3 weeks PC + ASA404 every ASA404 carboplatin/ ASA404 with pacli - ASA404 + chemother - ASA404 + taxans Study Docetaxel + ASA404 Fluvoxamine + ASA404 Docetaxel + ASA404 ASA404 + PC ASA404 + PC every TABLE 3 6 | DAEI FARSHCHI ADLI et al. Vadimezan was well tolerated by the patients under trials,

[55] [56] and the side-effects were similar to other combination therapy studies—such as peripheral neuropathy, neutropenia, injection site pain, and alopecia. PK parameters were con- sistent with those seen in non-Japanese patients. Cardiac NCT00738387 NCT01031212 NCT00662597 NCT01071928 NCT number (ref) cases were not observed except in three patients that had QT prolongation. Of all the patients receiving DMXAA, only three patients completed six cycles of treatment. Dose- limiting toxicity (DLT) incidence was less than one-third, Terminated Withdrawn Terminated Withdrawn Status which was seen in two patients. One patient had neutropenia with doses of 1,200 mg/m2, and the other patient had QTc prolongation with doses of 1,800 mg/m2. In this study, the level of plasma 5-hydroxyindole- 3- acetic acid exhibited an cell lung cancer. increase in the range of 116% to 204%, as the amount of the applied dose was increased from 1,200 to 1,800 mg/m 2, Not reported Not reported Well tolerated Not reported Main adverse effect respectively. Such result clearly implies the dose depen- stage small- dency of 5-hydroxyindole- 3- acetic acid increase. In four patients (27%), tumor response was seen, and in seven patients (47%), stable disease was detected.[51] In the second Japanese single-arm, open-label study, nine SCLC, extensive- patients with recurrent solid tumors in advanced level were treated with Vadimezan 1,800 mg/m2 and docetaxel 60 mg/ m2 (n = 3) or 75 mg/m2 (n = 6). The rate of DLTs was less than one-third patients; one patient had a partial response. Five patients (55.6%) showed having unchanging disease.[52]

1.6 | Phase II clinical trials of ASA404: analysis. analysis Trial was stopped for futility at the interim Trial was stopped for futility at the interim Not reported Not reported Results combination therapy

refractory metastatic prostate cancer; ES- Randomized, open-label, phase I/II study of DMXAA was ) 2 conducted on locally advanced and metastatic NSCLC patients. This study, sponsored by Antisoma Research, used DMXAA in combination with carboplatin plus paclitaxel.[53] As a cohort and single-arm extension for this trial, thirty Dosage (mg/m 1,800 1,800 — 1,800 patients with the same condition received 50% higher doses of DMXAA, 1,800 mg/m2 plus carboplatin and paclitaxel with the same doses. The partial tumor response rate in patients that was obtained through two separate assessments Enrollment 900 1,285 — — cell lung cancer; CRMPC, castration- (namely, independent assessment and investigators as-

small- sessment) turned out to be 37.9% and 46.7%, respectively. Higher doses of DMXAA improved median overall survival (OS) slightly (14.9 months). Overall, DMXAA and carbo- solid tumors Carcinoma Setting NSCLC NSCLC Refractory Urothelial platin plus paclitaxel were well tolerated by patients in both studies.[54] The side-effects were mostly attributed to the Phase III III II II carboplatin and paclitaxel, and no significant increase in toxicity was observed. Therefore, for subsequent evaluation in phase III studies, a dose of 1,800 mg/m2 DMXAA was recommended.[55] (Continued) In a randomized, multicenter study, the combination of docetaxel and Vadimezan was evaluated. In short, the outcome of this study was that the combination of docetaxel second line ATTRACT-2 ATTRACT-1 paclitaxel/cetuximab second line with DMXAA showed an acceptable toxicity without adverse Study Docetaxel + ASA404, PC + ASA404, first line ASA404 + Carboplatin/ Docetaxel + ASA404 [56] TABLE 3 PC, Paclitaxel and carboplatin; NSCLC, advanced non- drug interactions and elicited anti-CRMPC activities. DAEI FARSHCHI ADLI et al. | 7 In a multicenter, single-arm, phase II trial, sponsored by 2 EXPERT OPINION the Swiss Group for Clinical Cancer Research, seventeen | patients with extensive-stage small-cell lung cancer were One of the most prospective tumor-VDAs drugs is the treated with ASA404 (1,800 mg/m2) and carboplatin (area Vadimezan, DMXAA, which was synthesized as flavone-8 under curve = 6) plus paclitaxel (175 mg/m2) for 21 days acetic acid analogs. However, the potency and antitumor in six cycles. Although this phase III study was initially in- activity of Vadimezan have been seen to be much greater tended to be carried out on fifty-six patients with NSCLC, it than flavone-8 acetic acid. Even though in its clinical was prematurely/reluctantly stopped, before its completion, dosages, Vadimezan exhibits no significant toxicity, it mainly, because of obtaining disappointing inconsistent re- can irreversibly and profoundly prohibit the tumor blood sults from two separate NSCLC phase III studies. [60] flow. This unique prohibition of blood flow property The primary goal of this study was to achieve a of Vadimezan can desirably cause hemorrhagic necrosis progression-free survival (PFS) rate of 59% at 24 weeks, in tumor tissues of experimental models, without harm- which considered as a promising result to continue. [41] ing healthy vascular tissues. In vivo study, injection of However, at 24 weeks, PFS rate was only 41% (95% CI Vadimezan causes significant tumor responses in 80% of 18%–65%). Response to the tumor was 94%. The 1-year [61] tumor mice models. Pharmacokinetics of Vadimezan survival rate was 57%, and overall median survival time has been completely characterized, and it has been shown was 14.2 months (95% CI 8.2–16.0 months). Although the [62] to be very complex, but yet very predictable. It is very response rate was high, the combination of ASA404 and severely dose-dependent, and its plasma protein binding C/P did not result in an increased PFS. All toxicities were [57] is high but yet saturable. Also, in its higher doses, it can expected. [63,64] bind with other proteins present in red blood cells. Other preclinical studies have shown additional outcomes 1.7 | Phase III clinical trials of ASA404: for Vadimezan in combination with conventional cytotoxic combination therapy agents such as etoposide, carboplatin, taxanes, vincris- tine, doxorubicin, cyclophosphamide, cisplatin, paclitaxel, Promising results from phase I and phase II, especially on [49,65] and especially taxanes. Vadimezan does not signifi- patients with NSCLC, triggered the undertaking of two cantly change the pharmacokinetics of drugs such as pa- large, randomized, double-blind, placebo-controlled phase clitaxel, docetaxel, and carboplatin. Combination therapy III trials, using DMXAA in combination with paclitaxel of Vadimezan and paclitaxel/carboplatin in phase I/II for and Carboplatin chemotherapy—as briefly discussed in this the treatment of NSCLC improves tumor responses and study and extensively explained, by Hida T and McKeage, increases the 5-month median survival advantage, time to in their work, respectively.[51,53,55] These studies that were disease progression, and partial response in both patients sponsored by Novartis Pharmaceuticals, called ATTRACT-1 with squamous NSCLC and those with non-squamous (Antivascular Targeted Therapy: Researching ASA404) and [51,53,54] NSCLC. These promising results led ATTRACT-1 ATTRACT-2. In the ATTRACT-1 study, 1,299 patients and ATTRACT-2 to be designed and performed to visual- divided into the two groups of paclitaxel (200 mg/m2) and ize the functionality of Vadimezan in combination therapy carboplatin (area under the curve = 6.0) with or without with carboplatin/paclitaxel in the treatment of NSCLC. DMXAA (1,800 mg/m2), and were treated as first-line treat- The overall purpose of these experiments was to deter- ment intravenously every 3 weeks for six cycles. After six mine the significant overall amount of survival levels cycles of treatment, patients received either only ASA404 (OS). However, the primary analyses of the results failed or placebo. OS was the primary goal, and overall response to demonstrate the significant difference in the OS levels rate (ORR) and PFS were the secondary goals. The analy- between the Vadimezan group and the sham group, which, sis of the final results did not show significant differences in consequently, lead to the premature termination of the OS between the ASA404 and placebo groups—13.4 versus [58] experiment. 12.7 months, respectively. Median PFS was also reported An interesting question here is now: whether or not one in both groups 5.5 months and 25% ORR. Overall, although should be surprised by the results of phase III experiments, the drug was well tolerated in both groups, it failed to ex- considering the dramatic difference between the outcomes of hibit any efficacy to the addition of ASA404 to the stand- phase III experiments with those of phase II experiments? ard chemotherapy for the first-line treatment of advanced Maybe not. In fact, the difference observed in two different NSCLC.[58] Like ATTRACT-1, the study of ATTRACT-2 median OS (8.8 months versus 14 months)—which showed using Vadimezan or placebo with docetaxel (75 mg/m2) as the p value of .33 in combination therapy of ASA404 with pa- a second-line treatment of the same disease on 900 patients clitaxel/carboplatin—was the central motivation for the start was reluctantly stopped before its completion for similar [53] of phase III treatment studies. This means that there is a reasons.[59] 8 | DAEI FARSHCHI ADLI et al. little significant difference between the two different medians effects.[70] Furthermore, corticosteroids can also inhibit the OS. The notion of carrying out costly large-scale experiments antitumor activity of Vadimezan in macrophages.[71] On the in hope for achieving some minute beneficial outcomes does other hand, in a couple of phase II clinical trials of ASA404 not look like an economically wise undertaking. Similarly, and taxanes combination therapy performed on patients with such undertaking on only a specific population, rather than NSCLS, where corticosteroids in conjunction with ASA404 on a vast variety of populations, does not look like a logical and taxanes were simultaneously used, an increased anti- move. This scenario, consequently, brings us to the bigger tumor effects were seen.[53–55] Despite all the trials carried question: why Vadimezan does not have the expecting clini- out so far, the effects of simultaneous utilization of steroids cal outcome? to treat NSCLC are still unclear. Considering the resulting In this regard, some facts need to be pinpointed: Firstly, outcomes so far, it is clear that more clinical studies need to whether or not the functional mechanism of Vadimezan in be performed to fully understand the impact of simultaneous human and animal models is the same. In vivo studies have injection of Vadimezan and corticosteroids on both rats and shown a couple of first events, 24 hr after the injection of humans. Vadimezan in the mice model—including inhibition of blood The other issue which might affect the clinical results of flow, increased permeability, increased 5-HIAA, and induc- Vadimezan is the dilemma of whether or not the temporal tion of apoptosis.[20,45,66] On the other hand, the injection of aspects of the action of ASA404 have completely been con- Vadimezan in mice increases TNF amounts, but in human, sidered? In preclinical studies, the injection of Vadimezan this rise is almost zero, in most cases.[11] Although the rise was either simultaneous or after the injection of therapeutic in TNF amount is negligible in rat trials, the corresponding chemical drugs. The reason for such drug scheduling was to tumor response is considerably significant, especially when prevent the probable inhibitory effect of Vadimezan in the dosages larger than those utilized in human trials are used delivery of the chemical drug. Nevertheless, researchers have in rat trials. Unlike in In vivo study case, in In vitro study, speculated that even Vadimezan with its positive effects on Vadimezan stimulates human peripheral blood leukocytes to drug clearances might have a synergetic effect on the drug produce TNF.[42,67] efficiency.[48] In any respect, in long terms following the vas- These data demonstrate that, basically, Vadimezan should cular disrupture, Vadimezan causes hypoxia and, therefore, be active in humans. Because of this expectation, newer stud- induces angiogenesis and produces VEGF.[40] Now, the new ies are in search for finding the reasons for the disappoint- question is that whether or not anti-angiogenesis agents can ing phase III results. These studies have demonstrated that be utilized in conjunction with Vadimezan. The answer to STING receptors responsible for receiving Vadimezan signals this interesting question was, in fact, given in an annual meet- in mice are, in fact, not functional in humans. Xanthenone- ing of ASCO in 2006. In that meeting, it was announced that 4-acetic analogs severely demonstrate species-selectivity. the combination therapy of Vadimezan with bevacizumab Analogs active in mice are inactive in humans. This finding improves the effect of Vadimezan in a murine xenograft reiterates the necessities of the proper animal model to in- model with human lung and colon cancers.[72] Relying on the vestigate the effects of this class of drugs.[68] STING is the findings so far, it is, therefore, safe to say that performing direct receptor of Vadimezan, which starts TBK1 and IRF3 clinical experiments of combination therapy of Vadimezan in signaling. Surprisingly, sensitivity to STING receptors is lim- conjunction with anti-angiogenesis are considerably effective ited to murine species, and human STING is not capable of and could lead to quite desirable results. responding to Vadimezan.[31] This finding that Vadimezan The other thing, which seemed to have a role in cannot activate human STING is a strong deduction of the Vadimezan phase III disappointing results, was the kind disappointing clinical results.[69] of the tumor that went under treatment in clinical trials. The preceding discussion, naturally, raises the following Highly vascularized tumors have higher sensitivity to the question: are the method of injections in mice and human eradication of vasculature. The production of vasoactive clinical trials the same? The three chemical drugs of carbo- mediators such as VEGF leads to hypoxia and thus causes platin, docetaxel, and paclitaxel have been decisively cho- angiogenesis in the tumor. For instance, due to genetic sen for combination therapy of Vadimezan, based on the changes, renal cell carcinomas produce large amounts of convincing results.[49] However, there is a big difference VEGF so they can be very sensitive and exciting targets for between these two trials. Whereas, in Vadimezan trial, the Vadimezan therapy. In fact, it can be said that Vadimezan clinical trials that help inhibit both the unwanted side-effects has an unimportant effect on the normal vasculature. On the of drugs (i.e., vomiting) and high sensitivity to corticoste- other hand, we know that tumor vasculature is very much roids (such as dexamethasone) have been prescribed. In disorganized and non-homogenous.[73] The tumor center is preclinical and in vivo trials, it has not gone this way. The suffering from hypoxia, but the border of the tumor is more simultaneous injection of corticosteroids and Vascular dis- like a normal vasculature. So, responses to Vadimezan in rupting agent (VDA) drugs causes the inhibition of antitumor the viable rim region are reduced and are suitably called DAEI FARSHCHI ADLI et al. | 9 “viable ring” effect.[5,74,75] On the second thought, it can be and through a wise choices of other antitumor agents for said that “viable ring” effect is not specific for Vadimezan, combination therapy with Vadimezan, curing tumors can as the other drugs in this class of VDAs have the same become considerably effective and productive in the close drawback.[7] No matter how much the VDA drugs disrupt feature. tumor center vasculature, these drugs do not promise acceptable outcomes, as the peripheral tumor area can still CONFLICT OF INTEREST get the needed oxygen and nutrition from the close by healthy tissues, and, therefore, continue their undesirable None to declare. disruptions.[5] The viable rim region can clearly be viewed via microscopic techniques.[76] On the other hand, the pe- AUTHOR INFORMATION ripheral tumor region is the only area of the tumor to which novel therapeutic drugs with high molecular weights, such Nosratollah Zarghami is a chief professor of Medical as antibodies, have access; Thus, Vadimezan combination Biotechnology and Clinical Biochemistry, and a director of therapy with these drugs seems to be an interesting and the Department on Medical Biotechnology in the Faculty wise approach.[5] of Advanced Medical Sciences of Tabriz University of As such, Vadimezan combination therapy should not be Medical Sciences. His recent research interests include limited to taxanes. A good understanding of the exact mech- Molecular Targeted Therapy, Cancer Research, and anism of Vadimezan action and the result of Vadimezan Nanobiomedicine. monotherapy can be useful for designing a more effective Nosratollah Zarghami started his professorship at the and productive combination therapy. Interestingly, the drug school of advanced medical sciences in 2004. He has pub- Vadimezan itself causes hypoxia in the tumor, and this desir- lished more than 250 articles and guided more than 150 able phenomenon makes the tumor more sensitive to the treat- M.Sc. and Ph.D. students as an supervisor. ments that work more effectively under hypoxia condition. Thus, via appropriate timing and scheduling for Vadimezan ORCID combination therapy with radiotherapy, we can expect effective cure.[77] Moreover, due to its immune-stimulatory activ- Nosratollah Zarghami http://orcid. ity, Vadimezan has the potential for combination therapy with org/0000-0002-4236-4537 immunotherapy agents. The main problem with immunotherapy, although, is the size of tumors, which, fortunately, can REFERENCES be overcome by one of the available treatment methods, such as combination therapy. In short, Vadimezan can target the [1] L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-Tieulent, A. tumor center which is out of reach of immunotherapy, and, Jemal, CA Cancer J. Clin. 2015, 65, 87. CA Cancer J. Clin. 66 thereby, results in effective tumor treatment.[78] [2] R. L. Siegel, K. D. Miller, A. Jemal, 2016, , 7. [3] J. Denekamp, Acta Radiol. Oncol. 1984, 23, 217. [4] R. Jahanban-Esfahlan, M. de la Guardia, D. Ahmadi, B. Yousefi, 3 | CONCLUSIONS J. Cell. 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