Localization of sunitinib, its metabolites and its target receptors in tumour‐bearing mice: a MALDI‐MS imaging study. (12th January 2015)

• Record Type: Journal Article
• Authors: Torok, S; Vegvari, A; Rezeli, M; Fehniger, T E; Tovari, J; Paku, S; Laszlo, V; Hegedus, B; Rozsas, A; Dome, B; Marko‐Varga, G
• Is Part Of: British journal of pharmacology. Volume 172:Number 4(2015:Feb.)
• Page Start: 1148
• Page End: 1163
• Publication Date: 2015-01-12
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12990
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12990-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The clinical effects of anti‐angiogenic agents remain controversial. Therefore, elucidating the pharmacological properties of these compounds is a pivotal issue.</p> </sec> <sec id="bph12990-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>The effects of treatment with sunitinib on tumour and normal tissues of mice bearing C‐26 adenocarcinoma cells were analysed by matrix‐assisted laser desorption ionization MS imaging (MALDI‐MSI). Expression of the key targets of sunitinib – angiogenic receptors – was studied by immunofluorescent labelling.</p> </sec> <sec id="bph12990-sec-0003" sec-type="section"> <title>Key Results</title> <p>MALDI‐MS assays showed that sunitinib and its fragment ions were present throughout tumour and normal tissues. Major metabolites were identified in blood and solid tissues, while minor drug metabolites were detectable only in blood. Tumour growth and intratumour VEGF receptor‐2 expressions were significantly reduced in sunitinib‐treated mice, while the expression of the other targeted receptors, PDGF receptor ‐α or ‐β and fibroblast growth factor receptor‐1, remained unaffected. Within tumour tissue, the close proximity of sunitinib metabolites to the precursor ion suggested <italic>in situ</italic> metabolism of the administered drug. There were intratumour areas where the signal intensity of sunitinib correlated with expression of VEGF receptor‐2.</p> </sec> <sec id="bph12990-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>This is the first study that demonstrates MALDI‐MSI is a versatile platform to study the intratumour localization of an unlabelled anti‐angiogenic drug. The combination of MALDI‐MSI and immunofluorescence analysis can provide further insights into the molecular interaction of drug compounds and their targets within tumour tissue.</p> </sec> </abstract>