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Convection-enhancement delivery of platinum-based drugs and LipoplatinTM to optimize the concomitant effect with radiotherapy in F98 glioma rat model

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Summary

The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum-based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and LipoplatinTM - liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9- to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later.

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Acknowledgments

We would like to thank Dr. T. Boulikas for generously providing LipoplatinTM, Dr. A-M Crous-Tsanaclis for her assistance in reviewing the histological samples, and Dr. A.D. Bass for helpful suggestions and corrections.

Funding

This work was supported by Canadian Institutes of Health Research (grant # MOP 81356). David Fortin, Léon Sanche and Benoit Paquette are members of the Centre de Recherche du CHUS supported by the Fonds de la Recherche du Québec en Santé.

Conflict of interest

None

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Authors and Affiliations

  1. Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4

    Minghan Shi, Léon Sanche & Benoit Paquette

  2. Department of Surgery, Division of Neurosurgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4

    David Fortin

  3. Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Heath Science, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4

    Minghan Shi, Léon Sanche & Benoit Paquette

Authors
  1. Minghan Shi
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  2. David Fortin
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  4. Benoit Paquette
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Corresponding author

Correspondence to Benoit Paquette.

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Shi, M., Fortin, D., Sanche, L. et al. Convection-enhancement delivery of platinum-based drugs and LipoplatinTM to optimize the concomitant effect with radiotherapy in F98 glioma rat model. Invest New Drugs 33, 555–563 (2015). https://doi.org/10.1007/s10637-015-0228-4

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  • DOI: https://doi.org/10.1007/s10637-015-0228-4

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