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Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), in the brain and plasma

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Abstract

Purpose

Glioblastomas are amongst the most highly vascularised tumours, and the pursuit of anti-angiogenic approaches such as bevacizumab has provided short-term benefits. The purpose of this study was to determine whether the vascular-disrupting agent, dimethylxanthenone-4-acetic acid (DMXAA), could provide longer-lasting therapeutic benefits in a murine model of glioblastoma.

Methods

Luciferase-expressing murine GL261 glioma cells were inoculated subcutaneously or intracranially into C57Bl/6 mice. Mice with tumours were administered DMXAA, and tumours measured using callipers or by optical imager. Concentrations of DMXAA in plasma and brain were measured by LC–MS/MS.

Results

DMXAA (25 mg/kg) caused widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % of the mice with subcutaneous GL261 tumours. Co-administered lenalidomide (100 mg/kg) increased the growth delay to 20 days and the percentage of cures to 83 %. The same dose of DMXAA with or without lenalidomide had minimal effects on intracranial GL261 tumours. Concentrations of DMXAA extracted from brain tissue were approximately 25-fold lower than those measured in plasma 15 min to 4 h after DMXAA administration. The presence of intracranial GL261 tumours did not alter the concentrations of DMXAA entering the brain.

Conclusions

DMXAA does not appear to cross the blood–brain barrier efficiently. Thus, whilst excellent activity was obtained against subcutaneous GL261 gliomas, minimal effects were observed against intracranial GL261 tumours. These results emphasise the need to use appropriate orthotopic models for the evaluation of new approaches for the treatment of brain cancers.

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Acknowledgments

The authors would like to thank Drs Ian Hermans and Martin Hunn for their assistance in establishing the intracranial GL261 model. The study was funded by project grants from the Auckland Medical Research Foundation and the Cancer Society of New Zealand, Auckland Division.

Conflict of interest

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Author information

Authors and Affiliations

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

    Raymond Yung, Vahid Seyfoddin, Christopher Guise, Sofian Tijono & Lai-Ming Ching

  2. School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Ailsa McGregor

  3. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Bronwen Connor

  4. Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Ailsa McGregor & Bronwen Connor

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  1. Raymond Yung
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Correspondence to Lai-Ming Ching.

Electronic supplementary material

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280_2014_2395_MOESM1_ESM.tif

BLI of subcutaneous GL261 tumours in CD-1 nude mice on day 7, 10 and 15 after implantation (a). GL261 tumour volumes calculated from manual calliper measurements of tumour diameters (b). BLI measurements of the same tumours (c). Mean ± s.e.m. of six mice (TIFF 3523 kb)

280_2014_2395_MOESM2_ESM.tif

Representative whole brain from a mouse with day-7, day-10 or day-14 GL261 tumour (a). Relative BLI of intracranial GL261 tumours measured days 7, 10 and 15 after implantation, untreated (circles), lenalidomide (100 mg/kg) (triangles), DMXAA (25 mg/kg) (squares), and the combination of lenalidomide (100 mg/kg) with DMXAA (25 mg/kg) (diamonds). Points represent mean ± s.e.m. of six mice per group (b) (TIFF 1939 kb)

280_2014_2395_MOESM3_ESM.tif

Relative bioluminescence of intracranial GL261 tumours from individual animals over time, untreated (a), lenalidomide (100 mg/kg) (b), DMXAA (25 mg/kg) (c), or the combination of lenalidomide (100 mg/kg) with DMXAA (25 mg/kg) (d) over time (TIFF 1079 kb)

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Yung, R., Seyfoddin, V., Guise, C. et al. Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), in the brain and plasma. Cancer Chemother Pharmacol 73, 639–649 (2014). https://doi.org/10.1007/s00280-014-2395-y

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