Laboratory Investigation

Journal of Neuro-Oncology

, Volume 77, Issue 3, pp 225-232

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

  • Federico G. LegnaniAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins UniversityDepartment of Neurosurgery, School of Medicine, University of Milan
  • , Gustavo PradillaAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins UniversityDepartment of Oncology, School of Medicine, Johns Hopkins University
  • , Quoc-Anh ThaiAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins University
  • , Alessandro FiorindiAffiliated withDepartment of Neurosurgery, Ospedale Ca’ Foncello
  • , Pablo F. RecinosAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins University
  • , Betty M. TylerAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins University
  • , Sergio M. GainiAffiliated withDepartment of Neurosurgery, School of Medicine, University of Milan
  • , Francesco DiMecoAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins UniversityIstituto Nazionale Neurologico “Carlo Besta”
  • , Henry BremAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins UniversityDepartment of Oncology, School of Medicine, Johns Hopkins University
    • , Alessandro OliviAffiliated withDepartment of Neurosurgery, School of Medicine, Johns Hopkins UniversityDepartment of Oncology, School of Medicine, Johns Hopkins University

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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.

Keywords

animal model brain tumor controlled-release gliomas lactacystin local delivery polymer proteasome inhibitors