Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors
| Autor: | Ildiko Kovacs, Olga Kelemen, Sándor Paku, Walter Klepetko, Yutaka Sugihara, Melinda Rezeli, György Marko-Varga, Balazs Hegedus, Anna Tisza, Mir Alireza Hoda, Thomas H. Helbich, Timea Marton, Ákos Végvári, Thomas Klikovits, Ken-ichi Watanabe, Viktoria Laszlo, Balazs Dome, József Tóvári, Szilvia Török |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Sorafenib Vatalanib Angiogenesis Medizin Drug Resistance Medicine (miscellaneous) Angiogenesis Inhibitors Drug resistance Pharmacology imaging mass spectrometry resistance Pazopanib angiogenesis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Neoplasms medicine Motesanib cancer Animals Enzyme Inhibitors Pharmacology Toxicology and Pharmaceutics (miscellaneous) receptor tyrosine kinase inhibitor Sunitinib Vascular endothelial growth factor Disease Models Animal 030104 developmental biology chemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization 030220 oncology & carcinogenesis Research Paper matrix assisted laser desorption ionization medicine.drug |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.16767 |
| Popis: | 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. OA gold |
| Databáze: | OpenAIRE |
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