title: Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program.
abstract: BACKGROUND
  Cediranib (AZD2171) is a potent small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors. Cediranib has demonstrated single agent activity in several adult cancers and is being studied in combination with standard cytotoxic agents in multiple disease settings.
  
  
  METHODS
  Cediranib was tested in vivo against six childhood tumor xenograft models (four sarcomas, one glioblastoma, one neuroblastoma) alone or combined with cyclophosphamide (two models), vincristine (three models) or cisplatin (one model), each administered at its maximum tolerated dose, or rapamycin (six models).
  
  
  RESULTS
  The combination of cediranib with standard cytotoxic agents was superior to the cytotoxic agent used alone for a single xenograft (one of the three xenografts evaluated for the vincristine-cediranib combination). The cediranib-cyclophosphamide combination was inferior to single agent cyclophosphamide in time to event for both models studied and was significantly inferior for one of the models. Cediranib combined with rapamycin was superior to each of the agents used alone in two of the six models and was determined to be additive or supra-additive with rapamycin in four models, although the effects were not large.
  
  
  CONCLUSIONS
  Cediranib combined with cytotoxic chemotherapy agents demonstrated little or no benefit (and in one case was significantly inferior) compared to chemotherapy alone for the six pediatric cancer xenografts studied. By contrast, the combination of cediranib with rapamycin was additive or supra-additive in four of the six models in terms of prolongation of time to event, though tumor regressions were not observed for this combination.
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000293:Adolescent; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007223:Infant; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D000903:Antibiotics, Antineoplastic; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus; C500926:cediranib; D007211:Indoles