期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 172, 期 4, 页码 1148-1163出版社
WILEY
DOI: 10.1111/bph.12990
关键词
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资金
- Kutatasi es Technologiai Innovacios Alap (Research and Technology Innovation Fund) [AIK 12-1-2013-0041]
- Orszagos Kutatasi Tudomanyos Alapprogramok (Hungarian Scientific Research Fund) [K109626, K108465, MOB80325, K84173]
- ONB Jubilaumsfondsprojekt [14043]
- Vienna Fund for Innovative Interdisciplinary Cancer Research
- EACR Travel Fellowship
- Hungarian Pulmonology Foundation Research Fellowship
- Mrs. Berta Kamprad Foundation
- Ingabritt & Arne Lundbergs forskningsstiftelse
- Crafoord Foundation
- [EUREKA_HU_12-1-2012-0057]
Background and PurposeThe clinical effects of anti-angiogenic agents remain controversial. Therefore, elucidating the pharmacological properties of these compounds is a pivotal issue. Experimental ApproachThe 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. Key ResultsMALDI-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 - or - and fibroblast growth factor receptor-1, remained unaffected. Within tumour tissue, the close proximity of sunitinib metabolites to the precursor ion suggested in situ metabolism of the administered drug. There were intratumour areas where the signal intensity of sunitinib correlated with expression of VEGF receptor-2. Conclusions and ImplicationsThis 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.
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