title: Investigation of two dosing schedules of vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, in combination with irinotecan in a human colon cancer xenograft model.
abstract: OBJECTIVE
  This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer.
  
  
  METHODS
  HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib.
  
  
  RESULTS
  The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group.
  
  
  CONCLUSIONS
  These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.
authors.affiliation: Division of Medical Oncology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Henthorn
authors.forename: Owen
authors.initials: O
authors.lastname: Lockerbie
authors.forename: Andrea
authors.initials: A
authors.lastname: Merz
authors.forename: Michael
authors.initials: M
authors.lastname: Long
authors.forename: Mark
authors.initials: M
authors.lastname: Morrow
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D011799:Quinazolines; D000077146:Irinotecan; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D002166:Camptothecin; C452423:vandetanib