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

@article{Rustin200356Dimethylxanthenone4aceticA,
  title={5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study},
  author={G. Rustin and C. Bradley and S. Galbraith and M. Stratford and P. Loadman and S. Waller and K. Bellenger and L. Gumbrell and L. Folkes and G. Halbert},
  journal={British Journal of Cancer},
  year={2003},
  volume={88},
  pages={1160 - 1167}
}
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 m−2. The maximum tolerated dose was established at 3700 mg m−2; dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest… Expand
Pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (AS1404), a novel vascular disrupting agent, in phase I clinical trial
TLDR
The pharmacokinetics of DMXAA are well-defined, with a consistent degree of non-linearity across a very large dose range, and the main determinant of the non- linearity of the PK appeared to be sequential saturation of elimination mechanisms, which resulted in an exaggeratedNon-linear increase in freeDMXAA plasma concentrations and AUC compared to total drug. Expand
5,6-Dimethylxanthenone-4-Acetic Acid in the Treatment of Refractory Tumors: a Phase I Safety Study of a Vascular Disrupting Agent
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Doses in the range of 1,200 mg m−2 have been selected for further studies because this dose produced no significant effect on heart rate–corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated. Expand
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TLDR
DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen, and 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. Expand
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This review focuses on one of the vascular disrupting agents, 5-6-dimethylxanthenone 4-acetic acid (DMXAA), and the rationale for its combination with standard taxane-based chemotherapy. Expand
Improvement of the antitumor activity of intraperitoneally and orally administered 5,6-dimethylxanthenone-4-acetic acid by optimal scheduling.
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The use of a pharmacokinetically guided schedule provides excellent oral activity against Colon 38 tumors and provides a basis for developing more effective administration schedules in clinical trials. Expand
Population Pharmacokinetic-Pharmacodynamic Model of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid in Cancer Patients
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The present PK-PD model, with 5-HIAA as a biomarker, supports the use of DMXAA doses of 1,000 to 2,000 mg/m2 in phase II studies, and provides an example of how PK- PD models can be used to aid in selection of drug doses for phase II evaluation. Expand
Population Pharmacokinetic-Pharmacodynamic Model of the Vascular-DisruptingAgent 5,6-Dimethylxanthenone-4-Acetic Acid inCancer Patients
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Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours
TLDR
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How different scheduling of vadimezan could significantly enhance the anticancer efficacy of this drug in combination with other therapies, especially those that do not require concurrent corticosteroid administration is discussed. Expand
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References

SHOWING 1-10 OF 48 REFERENCES
Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.
TLDR
It is demonstrated that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity. Expand
Induction of tumour necrosis factor-α by single and repeated doses of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid
Abstract5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a low-molecular-weight biological response modifier scheduled for clinical evaluation, induced synthesis of tumour necrosis factor-α (TNF-α) inExpand
Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug.
TLDR
The kinetics of DMXAA glucuronidation in vivo are likely to be linear and unaffected by the coadministration of most glucuronidated drugs, but plasmaDMXAA clearance may be decreased in patients with renal dysfunction, illustrating the utility of in vitro techniques for the prediction of potential drug interactions and other dispositional characteristics of newly developed anticancer drugs before their administration to patients. Expand
Phase I and clinical pharmacology study of intravenous flavone acetic acid (NSC 347512).
TLDR
Dose-limiting toxicity was acute hypotension that began after about one-third of each drug dose had been infused and rarely lasted more than a few minutes after the infusion was discontinued; subjective fatigue and asthenia causing unacceptable patient discomfort was dose limiting. Expand
Preclinical in vitro and in vivo activity of 5,6-dimethylxanthenone-4-acetic acid.
TLDR
5,6-MeXAA was inactive against intraperitoneal MAC15A but produced significant anti-tumour effects against the same cell line inoculated via an intravenous route, and the effects against lung colonies were not accompanied by obvious necrotic changes, suggesting that they may be the result of increased direct cytotoxicity rather than an indirect host mechanism. Expand
Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver.
TLDR
It is demonstrated that DXAA undergoes extensive acyl glucuronidation followed by biliary excretion in the isolated perfused rat liver, and its hepatic metabolism may be saturable, and DXAA seems to be more extensively metabolized than FAA. Expand
Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.
TLDR
DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Expand
Serotonin involvement in the antitumour and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid
TLDR
It is suggested that serotonin is necessary for the induction of nitric oxide synthases and acts, either directly or indirectly, in concert with TNF. Expand
Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicine: relation to vascular effects.
TLDR
It is suggested that the increases in plasma serotonin and its metabolite are a result of drug-induced vascular effects in host tissues, and that measurement of these compounds provides a potential means of monitoring drugs exerting vascular effects. Expand
Combining bioreductive drugs (SR 4233 or SN 23862) with the vasoactive agents flavone acetic acid or 5,6-dimethylxanthenone acetic acid.
TLDR
DMXAA is a potent inhibitor of blood flow in MDAH-MCa-4 tumors and combination of this vasoactive drug with bioreductive agents leads to an enhanced antitumor effect. Expand
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