VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside
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Marlous Arjaans1, Carolina P. Schröder1, Sjoukje F. Oosting1, Urania Dafni2, Josée E. Kleibeuker3 and Elisabeth G.E. de Vries1
1 Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
2 Laboratory of Biostatistics, University of Athens, Athens, Greece
3 Department of Materials Science and Metallurgy, University of Cambridge, Cambridge, UK
Elisabeth G. E. de Vries, email:
Keywords: antiangiogenic drugs, blood vessel normalization, tumor drug delivery
Received: July 27, 2015 Accepted: December 05, 2015 Published: January 14, 2016
Vascular endothelial growth factor (VEGF) pathway targeting agents have been combined with other anticancer drugs, leading to improved efficacy in carcinoma of the cervix, stomach, lung, colon and rectum, ovary, and breast. Vessel normalization induced by VEGF pathway targeting agents influences tumor drug uptake. Following bevacizumab treatment, preclinical and clinical studies have shown a decrease in tumor delivery of radiolabeled antibodies and two chemotherapeutic drugs. The decrease in vessel pore size during vessel normalization might explain the decrease in tumor drug uptake. Moreover, the addition of bevacizumab to cetuximab, or panitumumab in colorectal cancer patients or to trastuzumab in breast cancer patients, did not improve efficacy. However, combining bevacizumab with chemotherapy did increase efficacy in some cancer types. Novel biomarkers to select patients who may benefit from combination therapies, such as the effect of an angiogenesis inhibitor on tumor perfusion, requires innovative trial designs and large clinical trials. Small imaging studies with radiolabeled drugs could be used in the interphase to gain further insight into the interplay between VEGF targeted therapy, vessel normalization and tumor drug delivery.
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