Universität zu Köln

Schiffmann, L. M., Brunold, M., Liwschitz, M., Goede, V., Loges, S., Wroblewski, M., Quaas, A., Alakus, H., Stippel, D., Bruns, C. J., Hallek, M., Kashkar, H., Hacker, U. T. and Coutelle, O. (2017). A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition. Br. J. Cancer, 116 (5). S. 600 - 609. LONDON: NATURE PUBLISHING GROUP. ISSN 1532-1827

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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 (0.5mgkg(-1) body weight) or high (5mgkg(-1) body 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schiffmann, L. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunold, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Liwschitz, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goede, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loges, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wroblewski, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alakus, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stippel, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, C. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kashkar, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hacker, U. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Coutelle, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-239456
DOI:	10.1038/bjc.2017.13
Journal or Publication Title:	Br. J. Cancer
Volume:	116
Number:	5
Page Range:	S. 600 - 609
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1532-1827
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language METASTATIC COLORECTAL-CANCER; ENDOTHELIAL GROWTH-FACTOR; INTERSTITIAL FLUID PRESSURE; ANTI-VEGF THERAPY; PULMONARY-FIBROSIS; PHASE-II; INHIBITION; TUMORS; CHEMOTHERAPY; LEUCOVORIN Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23945