title: VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside.
abstract: 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.
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Arjaans
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Schröder
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Sjoukje F
authors.initials: SF
authors.lastname: Oosting
authors.affiliation: Laboratory of Biostatistics, University of Athens, Athens, Greece.
authors.forename: Urania
authors.initials: U
authors.lastname: Dafni
authors.affiliation: Department of Materials Science and Metallurgy, University of Cambridge, Cambridge, UK.
authors.forename: Josée E
authors.initials: JE
authors.lastname: Kleibeuker
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A
keywords: antiangiogenic drugs; blood vessel normalization; tumor drug delivery