title: Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non-small-cell lung cancer xenograft models.
abstract: BACKGROUND
  Non-small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations.
  
  
  RESULTS
  Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro.
  
  
  CONCLUSIONS
  These data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.
authors.affiliation: Department of Oncology Research, Amgen Inc, One Amgen Centre Drive, Thousand Oaks, CA 91320, USA. acoxon@amgen.com
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Beth
authors.initials: B
authors.lastname: Ziegler
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaufman
authors.forename: Man
authors.initials: M
authors.lastname: Xu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wang
authors.forename: Dawn
authors.initials: D
authors.lastname: Weishuhn
authors.forename: Joanna
authors.initials: J
authors.lastname: Schmidt
authors.forename: Heather
authors.initials: H
authors.lastname: Sweet
authors.forename: Charlie
authors.initials: C
authors.lastname: Starnes
authors.forename: Douglas
authors.initials: D
authors.lastname: Saffran
authors.forename: Anthony
authors.initials: A
authors.lastname: Polverino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D000077143:Docetaxel; D005260:Female; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D040301:Vascular Endothelial Growth Factor Receptor-2; C519562:imetelstat; D002945:Cisplatin