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Lactacystin Exhibits Potent Anti-tumor Activity in an Animal Model of Malignant Glioma when Administered via Controlled-release Polymers

  • Laboratory Investigation
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Summary

Lactacystin, a proteasome-inhibitor, has been shown to induce apoptosis of experimental gliomas in vitro. However, its systemic toxicity prevents further clinical use. To circumvent this problem, lactacystin can be delivered intratumorally. We tested the efficacy of lactacystin incorporated into controlled-release polymers for treating experimental gliomas. 9L-gliosarcoma and F98-glioma cell lines were treated with lactacystin (10–100 μg/ml) for 72 h in vitro. Cell-viability was measured with MTT-assays. Toxicity of lactacystin/polycarboxyphenoxypropane-sebacic-acid (pCPP : SA) polymers was tested in vivo using Fischer-344 rats intracranially implanted with lactacystin polymers loaded from 0.1 to 2% lactacystin by weight. The efficacy of 1, 1.3, 1.5 and 1.7% lactacystin/pCPP : SA polymers was determined in Fischer-344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. Lactacystin was cytotoxic in 9L cells, causing a 16 ± 8% growth inhibition at 10-μg/ml that increased to 78 ± 4% at 100-μg/ml. Similarly, lactacystin inhibited growth of F98 by 18 ± 8% at 10-μg/ml and 74 ± 2% at 100-μg/ml in vitro. Polymers released lactacystin for 21 days and intracranial implantation in rats neither generate local nor systemic toxicity at doses lower than 2%. Treatment with lactacystin/pCPP : SA polymers with loading concentrations of 1.0, 1.3, and 1.5% prolonged survival of animals intracranially challenged with 9L when polymers where inserted in the day of tumor implantation. In conclusion, lactacystin exhibits potent cytotoxic-activity against 9L and F98 in vitro, it can be efficiently incorporated and delivered using controlled-release polymers, and at the proposed concentrations lactacystin polymers are safe for CNS delivery and prolong survival in the 9L model.

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Authors and Affiliations

  1. Department of Neurosurgery, School of Medicine, Johns Hopkins University, Italy

    Federico G. Legnani, Gustavo Pradilla, Quoc-Anh Thai, Pablo F. Recinos, Betty M. Tyler, Francesco DiMeco, Henry Brem & Alessandro Olivi

  2. Department of Oncology, School of Medicine, Johns Hopkins University, Italy

    Gustavo Pradilla, Henry Brem & Alessandro Olivi

  3. Department of Neurosurgery, School of Medicine, University of Milan, Italy

    Federico G. Legnani & Sergio M. Gaini

  4. Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy

    Francesco DiMeco

  5. Department of Neurosurgery, Ospedale Ca’ Foncello, Treviso, Italy

    Alessandro Fiorindi

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  1. Federico G. Legnani
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  2. Gustavo Pradilla
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  3. Quoc-Anh Thai
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  4. Alessandro Fiorindi
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  5. Pablo F. Recinos
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  6. Betty M. Tyler
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  7. Sergio M. Gaini
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  8. Francesco DiMeco
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  9. Henry Brem
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  10. Alessandro Olivi
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These authors equally contributed in all aspects of this study.

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Legnani, F.G., Pradilla, G., Thai, QA. et al. Lactacystin Exhibits Potent Anti-tumor Activity in an Animal Model of Malignant Glioma when Administered via Controlled-release Polymers. J Neurooncol 77, 225–232 (2006). https://doi.org/10.1007/s11060-005-6937-3

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  • DOI: https://doi.org/10.1007/s11060-005-6937-3

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