Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells

Anti-cancer Drugs
Erik BerglundRobert Bränström

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissue...Continue Reading

References

Mar 21, 2002·Nature Reviews. Cancer·Michael M GottesmanSusan E Bates
Sep 17, 2003·The Journal of Pharmacology and Experimental Therapeutics·Akinobu HamadaHideyuki Saito
Sep 20, 2006·Cancer Research·Sebastian BauerJonathan A Fletcher
Jun 24, 2010·Cancer Treatment Reviews·Heikki JoensuuPeter Reichardt
Jun 28, 2011·Electrophoresis·Anisa Elhamili, Jonas Bergquist

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Citations

May 16, 2014·Experimental Cell Research·Erik BerglundRobert Bränström
Jul 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Muhammad Suleman KhanAndrew A Somogyi
May 11, 2016·Clinical Biochemistry·Maria Shipkova, Dobrin Svinarov
Mar 31, 2018·Scientific Reports·Axel KlaessonUlf Landegren
Mar 19, 2019·Scandinavian Journal of Gastroenterology·Qiang ZhangZekuan Xu
Dec 21, 2016·Clinical Pharmacokinetics·Daniel T BarrattAndrew A Somogyi
Apr 16, 2021·Biochemical and Biophysical Research Communications·Robin FröbomRobert Bränström

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