title: Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma.
abstract: OBJECTIVE
  Lestaurtinib (CEP-701), a multi-kinase inhibitor with potent activity against the Trk family of receptor tyrosine kinases, has undergone early phase clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with isotretinoin (13cRA) and fenretinide (4HPR), two retinoids that have been studied in children with high-risk neuroblastoma.
  
  
  METHODS
  In vitro growth inhibition was assessed following a 72-hour drug exposure using the sulforhodamine B (SRB) assay in eight neuroblastoma cell lines with variable TrkB expression. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701.
  
  
  RESULTS
  The median (range) IC(50) of single-agent CEP-701 across all cell lines was 0.09 (0.08-0.3) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in four of the five cell lines studied. Addition of 1 or 5 μM of 13cRA decreased the median (range) CEP-701 IC(50) 1.5-fold (1.1-2.8-fold) and 1.7-fold (1.5-1.8-fold), respectively. With 10 μM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED(50) of 1.3 (1.1-1.5).
  
  
  CONCLUSIONS
  The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be potentially studied together in the setting of minimal residual disease following intensive chemoradiotherapy for children with high-risk neuroblastoma.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. norrisr@email.chop.edu
authors.forename: Robin E
authors.initials: RE
authors.lastname: Norris
authors.forename: Jane E
authors.initials: JE
authors.lastname: Minturn
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Brodeur
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002227:Carbazoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D017313:Fenretinide / Q000008:administration & dosage*; D005663:Furans; D006801:Humans; D015474:Isotretinoin / Q000008:administration & dosage*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D020813:Receptor, trkB / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D017313:Fenretinide; C119379:lestaurtinib; D020813:Receptor, trkB; D015474:Isotretinoin