Antivascular therapy of cancer: DMXAA

doi:10.1016/S1470-2045(03)01018-0

The Lancet Oncology

Volume 4, Issue 3, March 2003, Pages 141-148

https://doi.org/10.1016/S1470-2045(03)01018-0 Get rights and content

Summary

The vascular endothelium of tumour tissue, which differs in several ways from that of normal tissues, is a potential target for selective anticancer therapy. By contrast with antiangiogenic agents, antivascular agents target the endothelial cells of existing tumour blood vessels, causing distortion or damage and consequently decreasing tumour blood flow. DMXAA (5,6-dimethylxanthenone-4-acetic acid), a low-molecular-weight drug, has a striking antivascular and in some cases curative effect in experimental tumours. Its action on vascular endothelial cells seems to involve a cascade of events leading to induction of tumour haemorrhagic necrosis. These events include both direct and indirect effects, the latter involving the release of further vasoactive agents, such as serotonin, tumour necrosis factor, other cytokines, and nitric oxide from host cells. Phase I clinical trials of DMXAA have been completed and the next challenge to face is how the antivascular effect of this drug should be exploited for the treatment of human cancer.

Section snippets

Development of DMXAA

The development of DMXAA began with the finding that flavone acetic acid (figure 2), induces haemorrhagic necrosis of murine tumours.¹⁶ This substance was originally synthesised as a non-steroidal anti-inflammatory agent and was unexpectedly found to have excellent antitumour activity in preclinical experiments.¹⁷ It was subsequently found to have antivascular activity because of its ability to inhibit blood flow selectively in tumour tissue.9, 18, 19 However, it proved inactive in clinical

DMXAA and other antivascular agents

To understand the action of DMXAA more fully, we need to consider other agents that have been reported to induce vascular collapse and haemorrhagic necrosis of tumours. Studies have identified several classes of agents that target vascular endothelial cells and might therefore initiate the series of events shown in figure 1.

Cytokines that recognise receptors on endothelial cells are perhaps the most important class since they occur naturally in the body. These include TNF,³⁶ interleukin 1,³⁷

Physiological action of DMXAA

DMXAA shows outstanding experimental antitumour activity compared with other vascular agents. A possible reason for this activity is that it induces a cascade of antivascular events in tumour tissue (figure 3). Induced necrosis of tumour tissue requires inhibition of tumour blood flow for a time sufficient to deplete the cellular energy reserves needed to maintain plasma-membrane integrity. A cascade of events may be the most effective means of achieving this sustained effect. One of the

Molecular action of DMXAA

The biochemical target of DMXAA is still unknown, but there is substantial circumstantial evidence that its action involves pathways leading to the activation of nuclear-factor Bκ (NFκB, figure 5). DMXAA induces activation of NFκB in monocytes³² vascular endothelial cells,²⁷ and various tumour cells;⁶⁹ thus, it may mediate the direct effects of DMXAA on vascular endothelial cells and also cytokine synthesis in host and tumour cells. NFκB is thought to be the main transcription factor leading to

Perspective

DMXAA acts in vivo as an antivascular agent in both mice and human beings, but only modest evidence of antitumour activity has been obtained in clinical trials.³³ One possible explanation for the low activity in patients with cancer is that some of the steps in the antivascular cascade shown in figure 3 are not taking place. In clinical trials, induction of serum TNF was not detected and increases in plasma nitrate concentrations were small;³³ these findings are consistent with this hypothesis.

Search strategy and selection criteria

Searches of PubMed, Medline, OVID, and Embase were done with the terms “DMXAA”, “antivascular”, “cytokine”, “microcirculation”, “endothelial”, and “vascular permeability”.

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ReviewAntivascular therapy of cancer: DMXAA

Summary

Section snippets

Development of DMXAA

DMXAA and other antivascular agents

Physiological action of DMXAA

Molecular action of DMXAA

Perspective

Search strategy and selection criteria

Lancet Oncol

Exp Cell Res

Int J Radiat Oncol Biol Phys

Blood

Eur J Cancer Clin Oncol

Eur J Cancer Clin Oncol

Eur J Cancer

Clin Chim Acta

Curr Opin Immunol

Eur J Cancer

Eur J Cancer

Eur J Cancer

Surgery

Neoplasia

Endothelial proliferation in tumours and normal tissues: continuous labelling studies

Br J Cancer

TNF-alpha induces endothelial cell F-actin depolymerization, new actin synthesis, and barrier dysfunction

Am J Physiol

The tumournecrosis factor-alpha induced vascular permeability is associated with a reduction of VE-cadherin expression

Eur J Med Res

Determinants of tumor blood flow: a review

Cancer Res

Tumor necrosis factor induces apoptosis (programmed cell death) in normal endothelial cells in vitro

Am J Pathol

Blood flow failure as a major determinant in the antitumor action of flavone acetic acid (NSC 347512)

J Natl Cancer Inst

Platelet adhesion

Prog Hemost Thromb

Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicines: relation to vascular effects

Oncol Res

Important role of serotonin in the antitumor effects of tumor necrosis factor-alpha in mice

Cancer Res

Serotonin involvement in the antitumour and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid

Cancer Chemother Pharmacol

Delivery of novel therapeutic agents in tumors: physiological barriers and strategies

J Natl Cancer Inst

Flavone acetic acid (NSC 347512) induces haemorrhagic necrosis of mouse colon 26 and 38 tumours

Eur J Cancer Clin Oncol

Activity of flavone acetic acid (NSC-347512) against solid tumors of mice

Invest New Drugs

Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy

Cancer Res

Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy

J Natl Cancer Inst

Potential antitumor agents 60: relationships between structure and in vivo colon 38 activity for 5-substituted 9-oxoxanthene-4-acetic acids

J Med Chem

Potential antitumor agents 61: structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids

J Med Chem

Correlation between immune and vascular activities of xanthenone acetic acid antitumor agents

Oncol Res

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

Br J Cancer

Scintigraphic imaging of the hypoxia marker (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (Tc-99m-labeled HL-91; Prognox): noninvasive detection of tumor response to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

Cancer Res

Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

Br J Cancer

Induction of tumour necrosis factor-alpha by single and repeated doses of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid

Cancer Chemother Pharmacol

Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice

Cancer Res

Tumor-dependent increased plasma nitrate concentrations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in mice

Cancer Res

Induction of tumor necrosis factor-alpha messenger RNA in human and murine cells by the flavone acetic acid analogue 5,6-dimethylxanthenone-4-acetic acid (NSC 640488)

Cancer Res

Phase I pharmacokinetic and pharmacodynamic study of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent

Proc Am Soc Clin Oncol

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging

J Clin Oncol

The two different receptors for tumor necrosis factor mediate distinct cellular responses

Proc Natl Acad Sci USA

Review
Antivascular therapy of cancer: DMXAA