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Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours

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Abstract

Purpose

To evaluate the antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular disrupting agent currently under phase II clinical trials in combination with cancer chemotherapy, in rats bearing chemically induced primary mammary tumours.

Methods

Tumours were induced in female Wistar rats by injection of N-nitroso-N-methylurea at 100 mg/kg subcutaneously. A clinically relevant single dose of DMXAA (1,800 mg/m2) was given to animals when tumours were measurable. Tumour volume, extent of necrosis and cytokine profiles were measured.

Results

Compared with the control group, DMXAA treatment significantly delayed tumour doubling time and extended the time from treatment to euthanasia. Four of five DMXAA-treated animals showed necrosis involving 3.7–41.2% of the area of the tumour section at 24 h compared with none of four control animals (P < 0.028, Chi-square test). Intratumoural levels of TNFα, IL-6, VEGF and IL-1α were increased 4 h after DMXAA treatment.

Conclusions

This study shows for the first time that DMXAA has significant in vivo antitumour activity against non-transplanted autochthonous tumours and in a host species other than the mouse.

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Acknowledgments

The work was supported by New Zealand Cancer Society and the Auckland Medical Research Foundation. We wish to thank Prof. Michael Dragunow for his helpful assistance in imaging analysis (http://www.health.auckland.ac.nz/pharmacology/discovery-1/).

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand

    Johnson J. Liu, Michael Goldthorpe & Mark J. McKeage

  2. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Lai-Ming Ching, Rachel Sutherland, Bruce C. Baguley & James A. Kirker

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  1. Johnson J. Liu
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  2. Lai-Ming Ching
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  3. Michael Goldthorpe
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  4. Rachel Sutherland
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  5. Bruce C. Baguley
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  6. James A. Kirker
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  7. Mark J. McKeage
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Correspondence to Mark J. McKeage.

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Liu, J.J., Ching, LM., Goldthorpe, M. et al. Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours. Cancer Chemother Pharmacol 59, 661–669 (2007). https://doi.org/10.1007/s00280-006-0321-7

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  • DOI: https://doi.org/10.1007/s00280-006-0321-7

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