期刊
THERANOSTICS
卷 7, 期 2, 页码 400-412出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.16767
关键词
matrix assisted laser desorption ionization; imaging mass spectrometry; angiogenesis; receptor tyrosine kinase inhibitor; resistance; cancer
资金
- AIK [12-1-2013-0041]
- Hungarian National Research, Development and Innovation Office [K109626, K108465, SNN114490, K84173, K116295]
- Semmelweis University Start-Up grant [40148-11658]
- Vienna Fund for Innovative Interdisciplinary Cancer Research (BD)
- Hungarian Pulmonology Foundation Research Fellowship
- Ernst Mach-Stipendium
- Mrs. Berta Kamprad Foundation
- Ingabritt & Arne Lundbergs forskningsstiftelse
- Crafoord Foundation
- [2011-039226]
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.
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