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

Lash, C J; Li, A E; Rutland, M. D.; Baguley, Bruce C.; Zwi, L. Jonathan; Wilson, William R.

doi:10.1038/bjc.1998.512

Cited by 95 publications

(76 citation statements)

References 37 publications

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“…In this study, as in the parallel phase I study of DMXAA (Jameson et al, submitted), only a single unconfirmed tumour response was seen. Synergistic activity of DMXAA in combination with bioreductive cytotoxic drugs (Cliffe et al, 1994;Lash et al, 1998), chemotherapy (notably taxanes) (Pruijn et al, 1997;Horsman et al, 1999;Wilson and Baguley, 2000), thalidomide (Cao et al, 1999), immunotherapy (Kanwar et al, 2001), radiotherapy , and radioimmunotherapy (Pedley et al, 1999) has been demonstrated in animal models, and the potential of DMXAA in cancer treatment with its novel mechanism of action is likely to lie in combination therapy with other treatment modalities.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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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 À2 . The maximum tolerated dose was established at 3700 mg m À2 ; doselimiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg m À2 ). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 mM and 3.2 mM h, respectively, at 6 mg m À2 to 1290 mM and 7600 mM h at 3700 mg m À2 , while clearance declined from 7.4 to 1.7 l h À1 m À2 over the same dose range. The terminal half-life was 8.174.3 h. More than 99% of the drug was protein bound at doses up to 320 mg m À2 ; at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg m À2 . Dosedependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg m À2 and above. There was one unconfirmed partial response at 1300 mg m À2 . In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…Loss of tumour vascular endothelial cells by apoptosis would be expected to increase the permeability of the vascular endothelium, providing a potential mechanism for reduction in tumour blood flow (Baguley, 2001) as demonstrated in both murine models (Zwi et al, 1994a,b;Lash et al, 1998) and in clinical studies (Rustin et al, 1998). The results also provide a possible mechanism for the DMXAA-induced extravasation of erythrocytes in murine tumours (Zwi et al, 1994b).…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical studies, DMXAA was particularly effective against transplantable murine tumours with an established vasculature (Rewcastle et al, 1991), where it caused cessation of tumour blood flow, vascular collapse and tumour necrosis (Zwi et al, 1994a;Lash et al, 1998). DMXAA increased tumour necrosis factor (TNF) concentrations in plasma of both tumour bearing and non-tumour bearing mice (Philpott et al, 1995).…”

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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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“…Like FAA, DMXAA causes protracted inhibition of blood flow in murine tumours (Zwi et al, 1994;Lash et al, 1998) and induces extensive tumour haemorrhagic necrosis that is similar to that induced by TNF (Rewcastle et al, 1991). In situ hybridisation studies indicate that both host and tumour cells within murine colon 38 tumours express TNF mRNA after DMXAA treatment ).…”

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confidence: 99%

“…A significant decrease in tumour blood flow is observed within 1 h of administration of DMXAA, before detectable induction of cytokines (Zwi et al, 1994;Lash et al, 1998). Induced endothelial cell apoptosis in tumour tissue occurs as early as 15 min after DMXAA administration .…”

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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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

Cited by 95 publications

References 37 publications

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

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

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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