title: Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors.
abstract: Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies.
authors.affiliation: National Korányi Institute of Pulmonology, Budapest, Hungary;; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria;; Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden;; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Torok
authors.affiliation: Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden.
authors.forename: Melinda
authors.initials: M
authors.lastname: Rezeli
authors.affiliation: National Korányi Institute of Pulmonology, Budapest, Hungary;; Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Kelemen
authors.affiliation: Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden;; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Akos
authors.initials: A
authors.lastname: Vegvari
authors.affiliation: Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden;; Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sugihara
authors.affiliation: National Korányi Institute of Pulmonology, Budapest, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Tisza
authors.affiliation: National Korányi Institute of Pulmonology, Budapest, Hungary.
authors.forename: Timea
authors.initials: T
authors.lastname: Marton
authors.affiliation: National Korányi Institute of Pulmonology, Budapest, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Kovacs
authors.affiliation: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Tovari
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria;; Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Laszlo
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Helbich
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria;; Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, Germany;; Hungarian Academy of Sciences-Semmelweis University, Tumor Progression Research Group, Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klikovits
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors.forename: Mir Alireza
authors.initials: MA
authors.lastname: Hoda
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Hungarian Academy of Sciences-Semmelweis University, Tumor Progression Research Group, Budapest, Hungary;; 1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Sandor
authors.initials: S
authors.lastname: Paku
authors.affiliation: Clinical Protein Science&Imaging, Biomedical Center, Dept. of Biomedical Engineering, Lund University, Sweden;; Center of Excellence in Biological and Medical Mass Spectrometry, Lund University, Sweden.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Marko-Varga
authors.affiliation: National Korányi Institute of Pulmonology, Budapest, Hungary;; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria;; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary;; Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
authors.forename: Balazs
authors.initials: B
authors.lastname: Dome
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D004195:Disease Models, Animal; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors
keywords: angiogenesis; cancer; imaging mass spectrometry; matrix assisted laser desorption ionization; receptor tyrosine kinase inhibitor; resistance