title: Localization of sunitinib, its metabolites and its target receptors in tumour-bearing mice: a MALDI-MS imaging study.
abstract: OBJECTIVE
  The clinical effects of anti-angiogenic agents remain controversial. Therefore, elucidating the pharmacological properties of these compounds is a pivotal issue.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 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
  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.
authors.affiliation: Department of tumor Biology, National Korányi Institute of Pulmonology, Budapest, Hungary; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Clinical Protein Science and Imaging, Biomedical Center, Department of Biomedical Engineering, Lund University, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Torok
authors.forename: A
authors.initials: A
authors.lastname: Vegvari
authors.forename: M
authors.initials: M
authors.lastname: Rezeli
authors.forename: T E
authors.initials: TE
authors.lastname: Fehniger
authors.forename: J
authors.initials: J
authors.lastname: Tovari
authors.forename: S
authors.initials: S
authors.lastname: Paku
authors.forename: V
authors.initials: V
authors.lastname: Laszlo
authors.forename: B
authors.initials: B
authors.lastname: Hegedus
authors.forename: A
authors.initials: A
authors.lastname: Rozsas
authors.forename: B
authors.initials: B
authors.lastname: Dome
authors.forename: G
authors.initials: G
authors.lastname: Marko-Varga
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib