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

Jameson, Michael B.; Thompson, Paul; Baguley, Bruce C.; Evans, Barry J.; Harvey, Vernon; Porter, David; McCrystal, Michael R.; Small, Maurice J.; Bellenger, K; Gumbrell, Lindsey; Halbert, Gavin; Kestell, Philip

doi:10.1038/sj.bjc.6600992

Cited by 125 publications

(132 citation statements)

References 42 publications

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“…There was one unconfirmed partial response at 1300 mg m À2 . In a second study, in which 63 patients received 3-weekly infusions, comparable DLTs were observed with additional confusion, slurred speech, tremor and possible left ventricular failure (Jameson et al, 2003). Asymptomatic transient QTcprolongation was seen in 13 patients at high doses.…”

Section: Flavonoids Dmxaamentioning

confidence: 81%

Vascular disrupting agents in clinical development

2007

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Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

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Section: Flavonoids Dmxaamentioning

confidence: 81%

Vascular disrupting agents in clinical development

2007

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“…DMXAA was dissolved directly in culture medium for in vitro experiments. In the clinical phase trial conducted in Auckland, New Zealand, DMXAA was administered as a 20 min intravenous infusion on a 3-weekly schedule, using a pre-formulated solution of 20 mg ml 71 in 0.1 M phosphate buffer at pH 7.7 (Jameson et al, 2000). maintained under constant temperature and humidity according to institutional ethical guidelines and used between 8 -12 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast to the large increases in plasma TNF observed in mice treated with DMXAA, plasma TNF levels in patients treated in a Cancer Research UK phase I trial were not elevated (Jameson et al, 2000). However, dynamic contrast-enhanced magnetic resonance imaging suggested that tumour blood flow was inhibited in most patients receiving DMXAA at doses of 500 mg m 72 or higher (Rustin et al, 1998).…”

mentioning

confidence: 99%

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

et al. 2002

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5,6-Dimethylxanthenone-4-acetic acid, synthesised in this laboratory, reduces tumour blood flow, both in mice and in patients on Phase I trial. We used TUNEL (TdT-mediated dUTP nick end labelling) assays to investigate whether apoptosis induction was involved in its antivascular effect. 5,6-Dimethylxanthenone-4-acetic acid induced dose-dependent apoptosis in vitro in HECPP murine endothelial cells in the absence of up-regulation of mRNA for tumour necrosis factor. Selective apoptosis of endothelial cells was detected in vivo in sections of Colon 38 tumours in mice within 30 min of administration of 5,6-Dimethylxanthenone-4-acetic acid (25 mg kg −1 ). TUNEL staining intensified with time and after 3 h, necrosis of adjacent tumour tissue was observed. Apoptosis of central vessels in splenic white pulp was also detected in tumour-bearing mice but not in mice without tumours. Apoptosis was not observed in liver tissue. No apoptosis was observed with the inactive analogue 8-methylxanthenone-4-acetic acid. Positive TUNEL staining of tumour vascular endothelium was evident in one patient in a Phase I clinical trial, from a breast tumour biopsy taken 3 and 24 h after infusion of 5,6-Dimethylxanthenone-4-acetic acid (3.1 mg m −2 ). Tumour necrosis and the production of tumour tumour necrosis factor were not observed. No apoptotic staining was seen in tumour biopsies taken from two other patients (doses of 3.7 and 4.9 mg m −2 ). We conclude that 5,6-Dimethylxanthenone-4-acetic acid can induce vascular endothelial cell apoptosis in some murine and human tumours. The action is rapid and appears to be independent of tumour necrosis factor induction. British Journal of Cancer (2002) 86 , 1937–1942. doi: 10.1038/sj.bjc.6600368 www.bjcancer.com © 2002 Cancer Research UK

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“…DMXAA is known to induce interferons (Pang et al, 1998), IP-10 (Cao et al, 2001), serotonin (Baguley et al, 1993(Baguley et al, , 1997 and nitric oxide (Thomsen et al, 1991). Phase I trials of DMXAA show evidence of decreased tumour blood flow (Rustin et al, 1998;Jameson et al, 2000) and increased plasma 5HIAA ), but only a small increase in plasma nitrate and no increase in plasma TNF (Jameson et al, 2000). It is possible that other DMXAA-inducible cytokines are involved in humans, and their identification is an important consideration in future clinical trials.…”

Section: Experimental Therapeuticsmentioning

confidence: 99%

“…Flavone-8-acetic acid (FAA), and its more potent analogue 5,6-dimethylxanthenone-4-acetic acid (DMXAA), developed in this laboratory, are low molecular weight antivascular agents that appear to exert their antitumour effects at least partly through the induction of TNF (Mace et al, 1990;Philpott et al, 1995). FAA proved to be inactive in clinical studies (Kerr and Kaye, 1989), but DMXAA has shown evidence of activity in a Phase I clinical trial (Jameson et al, 2000).…”

mentioning

confidence: 99%

The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

Zhao

Kestell

et al. 2002

Br J Cancer

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5,6-dimethylxanthenone-4-acetic acid, a novel antivascular anticancer drug, has completed Phase I clinical trial. Its actions in mice include tumour necrosis factor induction, serotonin release, tumour blood flow inhibition, and the induction of tumour haemorrhagic necrosis and regression. We have used mice with a targeted disruption of the tumour necrosis factor receptor-1 gene as recipients for the colon 38 carcinoma to determine the role of tumour necrosis factor signalling in the action of 5,6-dimethylxanthenone-4-acetic acid. The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1 7/7 and wild-type mice. However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1 7/7 mice (4100 mg kg 71 ) than in wild-type mice (27.5 mg kg 71 ). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg 71 ) was strongly attenuated in tumour necrosis factor receptor-1 7/7 mice. However, the reduced toxicity in tumour necrosis factor receptor-1 7/7 mice allowed the demonstration that at a higher dose (50 mg kg 71 ), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg 71 ) in wild-type mice. The 5,6-dimethylxanthenone-4-acetic acid -induced rise in plasma 5-hydroxyindoleacetic acid, used to reflect serotonin production in a vascular response, was larger in colon 38 tumour bearing than in non-tumour bearing tumour necrosis factor receptor-1 7/7 mice, but in each case the response was smaller than the corresponding response in wild-type mice. The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies.

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

Cited by 125 publications

References 42 publications

Vascular disrupting agents in clinical development

Vascular disrupting agents in clinical development

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

The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

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