title: 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.
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Sampurna
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wieczorek
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Schöttle
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Siobal
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hinze
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Franz
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Adamczak
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Neumaier
authors.affiliation: Authors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, GermanyAuthors' Affiliations: Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne; Max Planck Institute for Neurological Research; Center for Molecular Medicine; Max Planck Institute for Biology of Aging; and Institute of Pathology, University Hospital Medical School, Cologne, Germany ullrich@nf.mpg.de.
authors.forename: Roland T
authors.initials: RT
authors.lastname: Ullrich
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; C404768:vatalanib; D000069347:Erlotinib Hydrochloride; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib