title: A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF)-targeting drugs normalise the tumour vasculature and improve access for chemotherapy. However, excessive VEGF inhibition fails to improve clinical outcome, and successive treatment cycles lead to incremental extracellular matrix (ECM) deposition, which limits perfusion and drug delivery. We show here, that low-dose VEGF inhibition augmented with PDGF-R inhibition leads to superior vascular normalisation without incremental ECM deposition thus maintaining access for therapy.
  
  
  METHODS
  Collagen IV expression was analysed in response to VEGF inhibition in liver metastasis of colorectal cancer (CRC) patients, in syngeneic (Panc02) and xenograft tumours of human colorectal cancer cells (LS174T). The xenograft tumours were treated with low (0.5 mg kg-1body weight) or high (5 mg kg-1body weight) doses of the anti-VEGF antibody bevacizumab with or without the tyrosine kinase inhibitor imatinib. Changes in tumour growth, and vascular parameters, including microvessel density, pericyte coverage, leakiness, hypoxia, perfusion, fraction of vessels with an open lumen, and type IV collagen deposition were compared.
  
  
  RESULTS
  ECM deposition was increased after standard VEGF inhibition in patients and tumour models. In contrast, treatment with low-dose bevacizumab and imatinib produced similar growth inhibition without inducing detrimental collagen IV deposition, leading to superior vascular normalisation, reduced leakiness, improved oxygenation, more open vessels that permit perfusion and access for therapy.
  
  
  CONCLUSIONS
  Low-dose bevacizumab augmented by imatinib selects a mature, highly normalised and well perfused tumour vasculature without inducing incremental ECM deposition that normally limits the effectiveness of VEGF targeting drugs.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, CECAD Research Centre, Joseph-Stelzmann-Street 26, 50931 Cologne, Germany.|Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany.|Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.
authors.forename: L M
authors.initials: LM
authors.lastname: Schiffmann
authors.affiliation: Department of Internal Medicine III, St Vinzenz Hospital, Merheimer Street 221-223, 50733 Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Brunold
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Bergisch Gladbach, Ferrenbergstr 24, 51465 Bergisch Gladbach, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Liwschitz
authors.affiliation: Department for Geriatric Medicine, St Marien Hospital, Kunibertskloster 11-13, 50668 Cologne, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Goede
authors.affiliation: Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Loges
authors.affiliation: Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wroblewski
authors.affiliation: Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.|Institute for Pathology, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Quaas
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany.|Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Alakus
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany.|Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Stippel
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany.|Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Bruns
authors.affiliation: Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.|Department I of Internal Medicine, University of Cologne, Kerpener Street 62, 50924 Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, CECAD Research Centre, Joseph-Stelzmann-Street 26, 50931 Cologne, Germany.|Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kashkar
authors.affiliation: University Medicine Leipzig, University Cancer Center Leipzig (UCCL), Liebigstr 20, 04103 Leipzig, Germany.
authors.forename: U T
authors.initials: UT
authors.lastname: Hacker
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, CECAD Research Centre, Joseph-Stelzmann-Street 26, 50931 Cologne, Germany.|Center for Integrated Oncology (CIO) Cologne-Bonn, Kerpener Street 62, Cologne 50924, Germany.|Department I of Internal Medicine, University of Cologne, Kerpener Street 62, 50924 Cologne, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Coutelle
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005109:Extracellular Matrix / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D024141:Collagen Type IV; D000068258:Bevacizumab; D000068877:Imatinib Mesylate