title: Antitumor activity of elacytarabine combined with bevacizumab, cetuximab and trastuzumab in human NSCLC xenografts.
abstract: OBJECTIVE
  The objective of the present study was to determine the in vivo antitumor activity of elacytarabine, the 5'-elaidic acid ester of arabinofuranosyl cytidine, alone and in combination with bevacizumab, cetuximab and trastuzumab in Vascular endothelial growth factor (VEGF), Epidermal growth factor receptor (EGFR)- and Human epidermal growth factor receptor 2 (HER2)-expressing non-small cell lung cancer xenografts.
  
  
  METHODS
  The antitumor activity of elacytarabine, was tested at the maximal tolerable dose (MTD; 50 mg/kg) and half MTD (25 mg/kg), alone and in combination with the antibodies bevacizumab (5 mg/kg), cetuximab (20 mg/kg) and trastuzumab (4 mg/kg) in two human non-small cell lung cancer xenografts.
  
  
  RESULTS
  Elacytarabine exhibited very high activity in the EKVX xenograft at both dose levels, but was inactive in MAKSAX. Neither of the two xenografts were sensitive to bevacizumab or trastuzumab, but the MAKSAX xenograft showed intermediate response to cetuximab. The high sensitivity of EKVX to elacytarabine precluded the assessment of a potential benefit of the combinations with the antibodies. In the elacytarabine-, bevacizumab- and trastuzumab-insensitive MAKSAX xenograft, the combination of either bevacizumab or trastuzumab with elacytarabine at the MTD or half MTD resulted in intermediate activity, suggesting a beneficial effect of the combinations, whereas for cetuximab, the effect was enhanced when combined with elacytarabine given at the MTD, but not half-MTD.
  
  
  CONCLUSIONS
  The results suggest that elacytarabine could be active in some cases of non-small cell lung cancer, and that the combination of elacytarabine and tyrosine kinase inhibitors may exert important additive or possibly synergistic effects of potential clinical benefit.
authors.affiliation: Deparment of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway. Skjalg.Bruheim@rr-research.no.
authors.forename: Skjalg
authors.initials: S
authors.lastname: Bruheim
authors.forename: Marit Liland
authors.initials: ML
authors.lastname: Sandvold
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000068818:Cetuximab; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003561:Cytarabine; C047645:5'-oleoyl cytarabine; D000068258:Bevacizumab; D000068878:Trastuzumab; D000068818:Cetuximab
keywords: Non-small cell lung cancer; bevacizumab; cetuximab; elacytarabine; in vivo antitumor activity; trastuzumab; xenograft