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Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem

Child's Nervous System volume 31, pages 557–562 (2015)Cite this article

Abstract

Purpose

Diffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high-grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small-molecule kinase inhibitors delivered to the mouse brainstem via convection-enhanced delivery (CED) for potential clinical application.

Methods

Effective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion.

Results

No animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity.

Conclusions

Brainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application.

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Funding

This study was supported by the Matthew Larson Foundation (to Z.Z.), New York Community Trust Research Grant (to M.M.S.), and St. Baldrick’s Foundation Summer Fellowship (to R.S.).

Author information

Affiliations

  1. Department of Neurological Surgery, Weill Medical College of Cornell University, 1300 York Ave, Box 99, New York, NY, 10065, USA

    Zhiping Zhou, Sharon L. Ho & Mark M. Souweidane

  2. Weill Medical College of Cornell University, New York, NY, USA

    Ranjodh Singh

  3. Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA

    David J. Pisapia

  4. Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA

    Mark M. Souweidane

  5. Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mark M. Souweidane

Authors
  1. Zhiping Zhou
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  2. Sharon L. Ho
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  3. Ranjodh Singh
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  4. David J. Pisapia
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  5. Mark M. Souweidane
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Corresponding author

Correspondence to Zhiping Zhou.

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Zhou, Z., Ho, S.L., Singh, R. et al. Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem. Childs Nerv Syst 31, 557–562 (2015). https://doi.org/10.1007/s00381-015-2640-7

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  • DOI: https://doi.org/10.1007/s00381-015-2640-7

Keywords

  • Convection-enhanced delivery
  • Diffuse intrinsic pontine glioma
  • Platelet-derived growth factor receptor
  • Small-molecule kinase inhibitor