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Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.

ABSTRACT: The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.

SUBMITTER: Jameson MB

PROVIDER: S-EPMC2741109 | biostudies-other | 2003 Jun

REPOSITORIES: biostudies-other

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5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study.

Project description:The purpose of this phase I, dose-escalation study was to determine the toxicity, maximum tolerated dose, pharmacokinetics, and pharmacodynamic end points of 5,6-dimethylxanthenone acetic acid (DMXAA). In all, 46 patients received a total of 247 infusions of DMXAA over 15 dose levels ranging from 6 to 4900 mg x m(-2). The maximum tolerated dose was established at 3700 mg x m(-2); dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg x m(-2)). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 microM and 3.2 microM h, respectively, at 6 mg x m(-2) to 1290 microM and 7600 microM h at 3700 mg x m(-2), while clearance declined from 7.4 to 1.7 l h(-1) x m(-2) over the same dose range. The terminal half-life was 8.1+/-4.3 h. More than 99% of the drug was protein bound at doses up to 320 mg x m(-2); at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg x m(-2). Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg x m(-2) and above. There was one unconfirmed partial response at 1300 mg x m(-2). In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

| S-EPMC2747563 | biostudies-other

The Chemotherapeutic Agent, 5,6-Dimethylxanthenone-4-Acetic Acid,

Project description:Vascular disrupting agents (VDA) represent a novel approach to the treatment of cancer, resulting in collapse of tumor vasculature and tumor death. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced Phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. The data presented herein demonstrate that DMXAA is a novel and specific activator of the TBK1-IRF-3 signaling pathway. DMXAA treatment of primary murine macrophages resulted in robust IRF-3 activation, a ~750-fold increase in IFN-beta mRNA and, in contrast to the potent Toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal NF-kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3, but MyD88-, TRIF-, IPS-1/MAVS-, and IKKbeta-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of murine macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid (SA). These findings detail a novel pathway for TBK-1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. Keywords: DMXAA, IRF-3, TBK1, IFN-beta, Salicylic acid, TLR

2007-03-08 | GSE7194 | GEO

Transcription profiling of mouse primary macrophages treated with the chemotherapeutic agent, 5,6-dimethylxanthenone-4-acetic acid,

Project description:Vascular disrupting agents (VDA) represent a novel approach to the treatment of cancer, resulting in collapse of tumor vasculature and tumor death. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced Phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. The data presented herein demonstrate that DMXAA is a novel and specific activator of the TBK1-IRF-3 signaling pathway. DMXAA treatment of primary murine macrophages resulted in robust IRF-3 activation, a ~750-fold increase in IFN-beta mRNA and, in contrast to the potent Toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal NF-kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3, but MyD88-, TRIF-, IPS-1/MAVS-, and IKKbeta-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of murine macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid (SA). These findings detail a novel pathway for TBK-1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. Experiment Overall Design: Microarray analysis was carried out using AffymetrixÂ® mouse array 430A_2 exposed to total RNA prepared from C57BL/6J or IFN-beta-/- macrophages that had been treated with medium alone or DMXAA for 3 h. Fold-induction was calculated using AffymetrixÂ® GeneChipÂ® Operating Software. A >3-fold increase or decrease between inducible and basal mRNA levels was set as the criteria for inclusion of a gene as modulated.

2008-06-15 | E-GEOD-7194 | biostudies-arrayexpress

Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

Project description:BackgroundSpecies selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models.MethodsAnalogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts.ResultsMono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems.ConclusionXanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds.

| S-EPMC3619269 | biostudies-literature

Activity of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid against human head and neck carcinoma xenografts.

Project description:Head and neck squamous cell carcinomas (HNSCC) constitute a majority of the tumors of the upper aerodigestive tract and continue to present a significant therapeutic challenge. To explore the potential of vascular-targeted therapy in HNSCC, we investigated the antivascular, antitumor activity of the potent vascular-disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against two HNSCC xenografts with markedly different morphologic and vascular characteristics. Athymic nude mice bearing subcutaneous FaDu (human pharyngeal squamous cell carcinoma) and A253 (human submaxillary gland epidermoid carcinoma) tumors were administered a single dose of DMXAA (30 mg/kg, i.p). Changes in vascular function were evaluated 24 hours after treatment using contrast-enhanced magnetic resonance imaging (MRI) and immunohistochemistry (CD31). Signal enhancement (E) and change in longitudinal relaxation rates (deltaR1) were calculated to measure alterations in vascular perfusion. MRI showed a 78% and 49% reduction in vascular perfusion in FaDu and A253 xenografts, respectively. CD31-immunostaining of tumor sections revealed three-fold (FaDu) and two-fold (A253) reductions in microvessel density (MVD) 24 hours after treatment. DMXAA was equally effective against both xenografts, with significant tumor growth inhibition observed 30 days after treatment. These results indicate that DMXAA may be clinically beneficial in the management of head and neck cancers, alone or in combination with other treatments.

| S-EPMC1601938 | biostudies-literature

Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid.

Project description:Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The antitumor activity of DMXAA has been linked to its ability to induce type I IFNs in macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator of IFN gene (STING) as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling. Remarkably, the ability to sense DMXAA was restricted to murine STING. Human STING failed to bind to or signal in response to DMXAA. Human STING also failed to signal in response to cyclic dinucleotides, conserved bacterial second messengers known to bind and activate murine STING signaling. Collectively, these findings detail an unexpected species-specific role for STING as a receptor for an anticancer drug and uncover important insights that may explain the failure of DMXAA in clinical trials for human cancer.

| S-EPMC3647383 | biostudies-literature

Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent.

Project description:Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against Entamoeba histolytica and Giardia intestinalis, major causes of water- and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and -resistant strains of Giardia We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p.o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (Cmax) at day 7 was 0.312 ?g/ml and the half-life (t1/2) 35 days, so steady-state blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 ?M (auranofin equivalent), or more than 25× the 50% inhibitory concentration (IC50) for E. histolytica and 4× that for Giardia, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 ?g/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broad-spectrum antiparasitic drug. (This study has been registered at ClinicalTrials.gov under identifier NCT02089048.).

| S-EPMC5192119 | biostudies-literature

Vadimezan: 2-(5,6-dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid.

Project description:In the title mol-ecule, C(17)H(14)O(4), the C atom of the carboxyl group deviates by 1.221?(3)?Å from the plane [maximum deviation = 0.0122(2)?Å] of the tricycic ring system. In the crystal structure, inter-molecular O-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, and ?-? inter-actions [centroid-centroid distances = 3.491?(3), 3.591?(3), 3.639?(3) and 3.735?(3)?Å] link these dimers into layers parallel to the ac plane. Weak inter-molecular C-H?O inter-actions further consolidate the crystal packing.

| S-EPMC3007383 | biostudies-literature

5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation.

Project description:5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xanthen-9-one (HHMX)-that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.

| S-EPMC10963404 | biostudies-literature

Phase I Clinical Trial of ES-285

Project description:Phase I Safety, Pharmacokinetic and Pharmacogenomic Trial of ES-285, a Novel Marine Cytotoxic Agent Administered as an Infusion over 24 h Every 21 Days in Patients with Solid Tumors Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Experimental design: Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4mg/m2. Dose escalation proceeded according to the worst toxicity observed in the previous cohort. Results: 28 patients were treated with 72 courses of ES-285 across 8 dose levels. No doselimiting toxicities (DLTs) were seen between 4mg/m2 and 128mg/m2. Two out of 4 patients treated at 256mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256mg/m2 also had transient grade 3 central neurotoxicity. One of 3 patients subsequently treated at 200mg/m2 died following drug-related central neurotoxicity. Pharmacokinetic studies indicated dose-proportionality with high volume of distribution (median Vss at 256mg/m2 was 2389L, range 1615-4051L) and long elimination half life (median t1/2 at 256mg/m2 was 29h, range 21-32h). The 3 patients with DLT had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Pre-treatment 59- and 49-gene sets were identified in blood and skin respectively, that may predict DLT. Disease stabilisation for 6 to 18 weeks was recorded in 9 patients. Conclusion: Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential biological relevance. Keywords: dose response

2009-04-01 | GSE12062 | GEO

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