title: Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurological Surgery, Weill Medical College of Cornell University, 1300 York Ave, Box 99, New York, NY, 10065, USA, zhz2004@med.cornell.edu.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhou
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Ho
authors.forename: Ranjodh
authors.initials: R
authors.lastname: Singh
authors.forename: David J
authors.initials: DJ
authors.lastname: Pisapia
authors.forename: Mark M
authors.initials: MM
authors.lastname: Souweidane
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000187:drug effects* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018481:Convection; D000069439:Dasatinib / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D000068338:Everolimus / Q000494:pharmacology; D005910:Glioma / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000139:chemically induced*; D051379:Mice; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; D000068338:Everolimus; D000069439:Dasatinib