title: Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H.
abstract: BACKGROUND
  Acquired resistance to imatinib is frequently caused by secondary KIT mutations. We have investigated the effects of imatinib in mice with human gastrointestinal stromal tumour (GIST) xenograft which harbours a primary exon 11 deletion mutation and a secondary imatinib resistance mutation D816H in exon 17. Such mutations are commonly present in imatinib-resistant GIST in humans.
  
  
  METHODS
  The mice were randomly allocated to receive imatinib either continuously or intermittently. Dynamic (18)F-FDG PET was performed and blood volume fraction (vB), rate transfer constants (k1, k2, k3) and metabolic rate of (18)F-FDG (MRFDG) were computed using a three-compartment model. Tumours were evaluated for the mitotic rate and the expression of HIF-1α , caspase-3 and glucose transporters (GLUTs).
  
  
  RESULTS
  Both intermittent and continuous imatinib delayed tumour growth significantly compared to controls, significantly in favour of the latter. k1 (representing perfusion, vascular permeability and binding of (18)F-FDG to the GLUTs) was significantly higher in the intermittent group compared to the continuous group, as was tumour GLUT-3 expression. k3 (representing internalisation of (18)F-FDG to the cells) and MR(FDG) were significantly lower.
  
  
  CONCLUSIONS
  Imatinib delays GIST xenograft growth despite the presence of the D816H resistance mutation. The schedule of imatinib administration may influence tumour glucose uptake rate and metabolic rate.
authors.affiliation: Department of Radiology and Nuclear Medicine, Oslo University Hospital, Nydalen, Oslo, Norway. mona.elisabeth.revheim@ous-hf.no
authors.forename: Mona-Elisabeth
authors.initials: ME
authors.lastname: Revheim
authors.forename: Alexandr
authors.initials: A
authors.lastname: Kristian
authors.forename: Eirik
authors.initials: E
authors.lastname: Malinen
authors.forename: Øyvind Sverre
authors.initials: ØS
authors.lastname: Bruland
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Berner
authors.forename: Ruth
authors.initials: R
authors.lastname: Holm
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Therese
authors.initials: T
authors.lastname: Seierstad
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001224:Aspartic Acid / Q000235:genetics; D001549:Benzamides / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006639:Histidine / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D001224:Aspartic Acid; D006639:Histidine; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit