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Transient antiangiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer.

Abstract
Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [(15)O]H2O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug.
AuthorsSampurna Chatterjee, Caroline Wieczorek, Jakob Schöttle, Maike Siobal, Yvonne Hinze, Thomas Franz, Alexandra Florin, Joanna Adamczak, Lukas C Heukamp, Bernd Neumaier, Roland T Ullrich
JournalCancer research (Cancer Res) Vol. 74 Issue 10 Pg. 2816-24 (May 15 2014) ISSN: 1538-7445 [Electronic] United States
PMID24675359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Angiogenesis Inhibitors
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
  • Phthalazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridines
  • Quinazolines
  • vatalanib
  • Erlotinib Hydrochloride
  • Receptors, Platelet-Derived Growth Factor
  • Receptors, Vascular Endothelial Growth Factor
Topics
  • Angiogenesis Inhibitors (administration & dosage, pharmacology)
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Carcinoma, Non-Small-Cell Lung (blood supply, drug therapy, enzymology)
  • Cell Line, Tumor
  • Drug Synergism
  • Erlotinib Hydrochloride
  • Humans
  • Lung Neoplasms (blood supply, drug therapy, enzymology)
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Nude
  • Multimodal Imaging
  • Phthalazines (administration & dosage, pharmacology)
  • Piperidines (administration & dosage, pharmacology)
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors (administration & dosage, pharmacology)
  • Pyridines (administration & dosage, pharmacology)
  • Quinazolines (administration & dosage, pharmacology)
  • Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
  • Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
  • Xenograft Model Antitumor Assays

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