Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H

Acta Oncol. 2013 May;52(4):776-82. doi: 10.3109/0284186X.2013.770920. Epub 2013 Mar 13.


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.

Material and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Aspartic Acid / genetics
  • Benzamides / administration & dosage*
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / genetics*
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Neoplasms / pathology
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / pathology
  • Histidine / genetics
  • Humans
  • Imatinib Mesylate
  • Mice
  • Mice, Nude
  • Mutation, Missense* / physiology
  • Piperazines / administration & dosage*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Pyrimidines / administration & dosage*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Aspartic Acid
  • Histidine
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit