Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H. (May 2013)

• Record Type: Journal Article
• Authors: Revheim, Mona-Elisabeth; Kristian, Alexandr; Malinen, Eirik; Bruland, Øyvind Sverre; Berner, Jeanne-Marie; Holm, Ruth; Joensuu, Heikki; Seierstad, Therese
• Is Part Of: Acta oncologica. Volume 52:Number 4(2013)
• Page Start: 776
• Page End: 782
• Publication Date: 2013-05
• Subjects: Oncology -- Periodicals; Cancer -- Treatment -- Periodicals; 616.992
• DOI: 10.3109/0284186X.2013.770920
• Languages: English
• ISSNs: 0284-186X

Abstract

<abstract> <title>Abstract</title> <p> <italic>Background</italic>. Acquired resistance to imatinib is frequently caused by secondary <italic>KIT</italic> 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. <italic>Material and methods</italic>. The mice were randomly allocated to receive imatinib either continuously or intermittently. Dynamic <sup>18</sup>F-FDG PET was performed and blood volume fraction (<italic>v</italic><sub><italic>B</italic></sub>), rate transfer constants (<italic>k</italic><sub>1</sub>, <italic>k</italic><sub>2</sub>, <italic>k</italic><sub>3</sub>) and metabolic rate of <sup>18</sup>F-FDG (<italic>MR</italic><sub><italic>FDG</italic></sub>) 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). <italic>Results.</italic> Both intermittent and continuous imatinib delayed tumour growth significantly compared to controls, significantly in favour of the latter. <italic>k</italic><sub>1</sub> (representing perfusion, vascular permeability and binding of <sup>18</sup>F-FDG to the GLUTs) was significantly higher in the intermittent group compared to the continuous group, as was tumour GLUT-3 expression. <italic>k</italic><sub>3</sub> (representing internalisation of <sup>18</sup>F-FDG to the cells) and <italic>MR</italic><sub><italic>FDG</italic></sub> were significantly lower. <italic>Conclusion.</italic> 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.</p> </abstract>