The morphological effects of the anti–tumor agents flavone acetic acid and 5,6–dimethyl xanthenone acetic acid on the colon 38 mouse tumor

Zwi, L. Jonathan; Baguley, Bruce C.; Gavin, J.B.; Wilson, William R.

doi:10.1080/00313029400169411

Cited by 19 publications

(7 citation statements)

References 30 publications

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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). Although a number of studies have implicated TNF in the antitumour response of DMXAA (Browne et al, 1998;Cao et al, 1999), three observations in this study support a TNF-independent action of DMXAA on the vascular endothelium.…”

Section: Discussionsupporting

confidence: 52%

“…The clinical trial results differ from those of murine studies in that although TNF synthesis was detected in one human tumour sample (Jameson et al, 2000) the level was low and TNF was not detected in the sample in which endothelial cell apoptosis was observed. Widespread haemorrhagic necrosis is a prominent effect of DMXAA treatment in murine tumours (Baguley et al, 1989;Zwi et al, 1994b;Cao et al, 1999) but has not so far been observed in clinical trials. In the Colon 38 tumour, in situ TNF synthesis is probably responsible for sustaining the vascular effect of DMXAA and inducing haemorrhagic necrosis.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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“…2,3 Their effects on tumour blood flow can also be exploited to enhance the efficacy of other therapies, for example 5,6-dimethylxanthenone-4-acetic acid (DMXAA) has been used to enhance antibody-directed enzyme prodrug therapy by trapping the antibodyenzyme conjugate or drug within the tumour. 4 Combretastatin A4 phosphate (CA4P) and DMXAA, which have both been shown to damage tumour vasculature in murine tumour models, resulting in reduced perfusion [5][6][7] and haemorrhagic necrosis of tumour tissue, 8,9 are currently in Phase I clinical trials. 6,10 CA4P, which is a tubulin-binding agent, has been shown to depolymerize the tubulin cytoskeleton and induce apoptosis in proliferating endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Differential sensitivity of two adenocarcinoma xenografts to the anti‐vascular drugs combretastatin A4 phosphate and 5,6‐dimethylxanthenone‐4‐acetic acid, assessed using MRI and MRS

et al. 2002

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The effects of two anti-vascular agents, combretastatin A4 phosphate (CA4P), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), on the perfusion of two human colon adenocarcinomas implanted in SCID mice, were assessed for up to 3 h using non-invasive magnetic resonance imaging (MRI) and spectroscopy techniques (MRS). MRI measurements of GdDTPA inflow showed that treatment with CA4P had little effect on the perfusion of HT29 tumours. Localized 31 P MRS measurements also showed that the drug had no significant effect on tumour cell energy status, as assessed from the ratio of the integrals of the signals from inorganic phosphate (P i ) and nucleoside triphosphates. However, after treatment with DMXAA, perfusion was reduced and the P i /NTP ratio increased, indicating that the HT29 tumour is susceptible to the action of this drug. The LS174T tumour model was susceptible to both CA4P and DMXAA, using the criteria of changes in GdDTPA inflow and P i /NTP ratio.

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“…The mechanism of antitumour action of DMXAA, like that of FAA, differs from that of directly cytotoxic drugs. 5,6-Dimethylxanthenone acetic acid has selective activity in targeting tumour vasculature in vivo, producing vascular shutdown, reducing tumour blood flow, and consequently causing haemorrhagic necrosis (Zwi et al, 1994b;Laws et al, 1995).…”

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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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The morphological effects of the anti–tumor agents flavone acetic acid and 5,6–dimethyl xanthenone acetic acid on the colon 38 mouse tumor

Cited by 19 publications

References 30 publications

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

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

Differential sensitivity of two adenocarcinoma xenografts to the anti‐vascular drugs combretastatin A4 phosphate and 5,6‐dimethylxanthenone‐4‐acetic acid, assessed using MRI and MRS

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

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