Shoraku Ryu1,2, Mitsuhiro Hayashi1,3, Hiroaki Aikawa1,3, Isamu Okamoto4, Yasuhiro Fujiwara5, Akinobu Hamada1,3,2,6. 1. Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Pharmacology and Therapeutics, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan. 3. Division of Clinical Pharmacology and Translational Research Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Tokyo, Japan. 4. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 5. Strategic Planning Bureau, National Cancer Center, Tokyo, Japan. 6. Department of Medical Oncology and Translational Research, Graduate school of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Abstract
BACKGROUND AND PURPOSE: The penetration of the anaplastic lymphoma kinase (ALK) inhibitor alectinib in neuroblastomas and the relationship between alectinib and ALK expression are unknown. The aim of this study was to perform a quantitative investigation of the inter- and intra-tumoural distribution of alectinib in different neuroblastoma xenograft models using matrix-assisted laser desorption ionization MS imaging (MALDI-MSI). EXPERIMENTAL APPROACH: The distribution of alectinib in NB1 (ALK amplification) and SK-N-FI (ALK wild-type) xenograft tissues was analysed using MALDI-MSI. The abundance of alectinib in tumours and intra-tumoural areas was quantified using ion signal intensities from MALDI-MSI after normalization by correlation with LC-MS/MS. KEY RESULTS: The distribution of alectinib was heterogeneous in neuroblastomas. The penetration of alectinib was not significantly different between ALK amplification and ALK wide-type tissues using both LC-MS/MS concentrations and MSI intensities. Normalization with an internal standard increased the quantitative property of MSI by adjusting for the ion suppression effect. The distribution of alectinib in different intra-tumoural areas can alternatively be quantified from MS images by correlation with LC-MS/MS. CONCLUSION AND IMPLICATIONS: The penetration of alectinib into tumour tissues may not be homogenous or influenced by ALK expression in the early period after single-dose administration. MALDI-MSI may prove to be a valuable pharmaceutical method for elucidating the mechanism of action of drugs by clarifying their microscopic distribution in heterogeneous tissues.
BACKGROUND AND PURPOSE: The penetration of the anaplastic lymphoma kinase (ALK) inhibitor alectinib in neuroblastomas and the relationship between alectinib and ALK expression are unknown. The aim of this study was to perform a quantitative investigation of the inter- and intra-tumoural distribution of alectinib in different neuroblastoma xenograft models using matrix-assisted laser desorption ionization MS imaging (MALDI-MSI). EXPERIMENTAL APPROACH: The distribution of alectinib in NB1 (ALK amplification) and SK-N-FI (ALK wild-type) xenograft tissues was analysed using MALDI-MSI. The abundance of alectinib in tumours and intra-tumoural areas was quantified using ion signal intensities from MALDI-MSI after normalization by correlation with LC-MS/MS. KEY RESULTS: The distribution of alectinib was heterogeneous in neuroblastomas. The penetration of alectinib was not significantly different between ALK amplification and ALK wide-type tissues using both LC-MS/MS concentrations and MSI intensities. Normalization with an internal standard increased the quantitative property of MSI by adjusting for the ion suppression effect. The distribution of alectinib in different intra-tumoural areas can alternatively be quantified from MS images by correlation with LC-MS/MS. CONCLUSION AND IMPLICATIONS: The penetration of alectinib into tumour tissues may not be homogenous or influenced by ALK expression in the early period after single-dose administration. MALDI-MSI may prove to be a valuable pharmaceutical method for elucidating the mechanism of action of drugs by clarifying their microscopic distribution in heterogeneous tissues.
Authors: Paul Slobbe; Albert D Windhorst; Marijke Stigter-van Walsum; Robert C Schuit; Egbert F Smit; Heiko G Niessen; Flavio Solca; Gerd Stehle; Guus A M S van Dongen; Alex J Poot Journal: Nucl Med Biol Date: 2014-06-25 Impact factor: 2.408
Authors: Michael J Curtis; Richard A Bond; Domenico Spina; Amrita Ahluwalia; Stephen P A Alexander; Mark A Giembycz; Annette Gilchrist; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Andrew J Lawrence; David J MacEwan; Lawrence D F Moon; Sue Wonnacott; Arthur H Weston; John C McGrath Journal: Br J Pharmacol Date: 2015-07 Impact factor: 8.739
Authors: Anna Nilsson; Thomas E Fehniger; Lena Gustavsson; Malin Andersson; Kerstin Kenne; György Marko-Varga; Per E Andrén Journal: PLoS One Date: 2010-07-14 Impact factor: 3.240
Authors: A A Memon; B Weber; M Winterdahl; S Jakobsen; P Meldgaard; H H T Madsen; S Keiding; E Nexo; B S Sorensen Journal: Br J Cancer Date: 2011-11-17 Impact factor: 7.640