Necrosis in non-tumour tissues caused by flavone acetic acid and 5,6-dimethyl xanthenone acetic acid

Zwi, L. Jonathan; Bc, Baguley; Gavin, JB; Wilson, WR

doi:10.1038/bjc.1990.412

Cited by 14 publications

(7 citation statements)

References 13 publications

(20 reference statements)

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“…However, cytolytic effects (either apoptosis or necrosis) were seen in gut lymphoid tissues, lymph nodes, spleen, thymus and uterus, which have in common with tumors a sparse vascular supply and a high content of macrophages or neutrophils. 34 The present studies do not explain the mechanism of FAA-induced perfusion failure, but important negative findings have emerged. There appears to be no selective damage to endothelial ceils; indeed, they show no visible response even when adjacent tumor cells are undergoing Pathology (1994), 26, April apoptosis in response to FAA (Fig.…”

Section: Discussionmentioning

confidence: 83%

“…The toxic effects of FAA in humans include dose-limiting hypotension and diarrhea, and toxic effects of FAA and DMX have been documented in animals (reviewed by Zwi et al). 34 Histological examination of non-tumor mouse tissues after therapeutic doses of FAA and DMX shows that most normal tissues are not sensitive to these drugs. However, cytolytic effects (either apoptosis or necrosis) were seen in gut lymphoid tissues, lymph nodes, spleen, thymus and uterus, which have in common with tumors a sparse vascular supply and a high content of macrophages or neutrophils.…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 1994

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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

et al. 1994

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“…The mechanism of DMXAA host toxicity has not yet been clearly defined but studies of tissue pathology in mice treated with DMXAA indicate that vascular damage can occur, particularly in tissues with a low vascular density such as peripheral lymphoid tissues, the thymus gland and the uterus (Zwi et al, 1990). Mice administered DMXAA at the MTD may exhibit sluggish move- Growth delays and cures include data from Figure 2 and from one independent experiment.…”

Section: Discussionmentioning

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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“…These approaches seem to have some efficacy, but rarely induce cures. Our group has conducted studies of TAM activation using a compound called 5,6-Dimethylxanthenone-4-acetic acid (DMXAA, Vadimezan), which is a small flavanoid-like compound that was originally developed as a vascular-disrupting agent (Zwi et al , 1990). Although endothelial cells may be directly affected, we and others found that DMXAA has powerful effects on the tumour microenvironment in mouse tumour models (Ching et al , 1999; Jassar et al , 2005; Roberts et al , 2007; Wallace et al , 2007).…”

mentioning

confidence: 99%

Using macrophage activation to augment immunotherapy of established tumours

et al. 2013

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Background:Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy.Methods:We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT–PCR).Results:In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8+ T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect.Conclusion:Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.

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Necrosis in non-tumour tissues caused by flavone acetic acid and 5,6-dimethyl xanthenone acetic acid

Abstract: Images Figure 1 Figure 2

Cited by 14 publications

References 13 publications

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

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

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

Using macrophage activation to augment immunotherapy of established tumours

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