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Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors

Torok, Szilvia; Rezeli, Melinda LU ; Kelemen, Olga LU ; Vegvari, Akos LU ; Watanabe, Kenichi LU ; Sugihara, Yutaka LU ; Tisza, Anna; Marton, Timea; Kovacs, Ildiko and Tovari, Jozsef, et al. (2017) In Theranostics 7(2). p.400-412
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... (More)

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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publication status
published
subject
keywords
Angiogenesis, Cancer, Imaging mass spectrometry, Matrix assisted laser desorption ionization, Receptor tyrosine kinase inhibitor, Resistance
in
Theranostics
volume
7
issue
2
pages
13 pages
publisher
Ivyspring International Publisher
external identifiers
  • scopus:85008425346
  • wos:000396555900013
DOI
10.7150/thno.16767
language
English
LU publication?
yes
id
32b2d88d-8c9e-4925-ad9a-a66b68684c25
date added to LUP
2017-02-06 10:49:04
date last changed
2018-04-08 04:53:40
@article{32b2d88d-8c9e-4925-ad9a-a66b68684c25,
  abstract     = {<p>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.</p>},
  author       = {Torok, Szilvia and Rezeli, Melinda and Kelemen, Olga and Vegvari, Akos and Watanabe, Kenichi and Sugihara, Yutaka and Tisza, Anna and Marton, Timea and Kovacs, Ildiko and Tovari, Jozsef and Laszlo, Viktoria and Helbich, Thomas H. and Hegedus, Balazs and Klikovits, Thomas and Hoda, Mir Alireza and Klepetko, Walter and Paku, Sandor and Marko-Varga, Gyorgy and Dome, Balazs},
  keyword      = {Angiogenesis,Cancer,Imaging mass spectrometry,Matrix assisted laser desorption ionization,Receptor tyrosine kinase inhibitor,Resistance},
  language     = {eng},
  number       = {2},
  pages        = {400--412},
  publisher    = {Ivyspring International Publisher},
  series       = {Theranostics},
  title        = {Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors},
  url          = {http://dx.doi.org/10.7150/thno.16767},
  volume       = {7},
  year         = {2017},
}