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Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model

  • Lab. Investigation-human/animal tissue
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Abstract

With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 ± 5% (mean ± SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 ± 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10–fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.

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Acknowledgements

This work was supported by the Andrew Olle Foundation, Department of Medical Oncology, and the Bill Walsh Cancer Research Trust, Royal North Shore Hospital, Sydney, Australia.

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Authors and Affiliations

  1. Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, 2065, Australia

    Susan Murphy, Ross A. Davey, Miriam C. Haywood & Lauren A. McCann

  2. Department of Anaesthesia and Pain Management, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, 2065, Australia

    Xiao-Qing Gu & Laurence E. Mather

  3. Medical Oncology Department, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, 2065, Australia

    Frances M. Boyle

Authors
  1. Susan Murphy
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  2. Ross A. Davey
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  3. Xiao-Qing Gu
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  4. Miriam C. Haywood
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  5. Lauren A. McCann
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  6. Laurence E. Mather
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  7. Frances M. Boyle
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Correspondence to Ross A. Davey.

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Murphy, S., Davey, R.A., Gu, XQ. et al. Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model. J Neurooncol 85, 181–189 (2007). https://doi.org/10.1007/s11060-007-9406-3

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  • DOI: https://doi.org/10.1007/s11060-007-9406-3

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