title: Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake.
abstract: In solid tumors, angiogenesis occurs in the setting of a defective vasculature and impaired lymphatic drainage that is associated with increased vascular permeability and enhanced tumor permeability. These universal aspects of the tumor microenvironment can have a marked influence on intratumoral drug delivery that may often be underappreciated. In this study, we investigated the effect of blood vessel normalization in tumors by the antiangiogenic drug bevacizumab on antibody uptake by tumors. In mouse xenograft models of human ovarian and esophageal cancer (SKOV-3 and OE19), we evaluated antibody uptake in tumors by positron emission tomographic imaging 24 and 144 hours after injection of (89)Zr-trastuzumab (SKOV-3 and OE19), (89)Zr-bevacizumab (SKOV-3), or (89)Zr-IgG (SKOV-3) before or after treatment with bevacizumab. Intratumor distribution was assessed by fluorescence microscopy along with mean vessel density (MVD) and vessel normalization. Notably, bevacizumab treatment decreased tumor uptake and intratumoral accumulation compared with baseline in the tumor models relative to controls. Bevacizumab treatment also reduced MVD in tumors and increased vessel pericyte coverage. These findings are clinically important, suggesting caution in designing combinatorial trials with therapeutic antibodies due to a possible reduction in tumoral accumulation that may be caused by bevacizumab cotreatment.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700RB Groningen, the Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Arjaans
authors.forename: Thijs H
authors.initials: TH
authors.lastname: Oude Munnink
authors.forename: Sjoukje F
authors.initials: SF
authors.lastname: Oosting
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
authors.forename: Erik T
authors.initials: ET
authors.lastname: Garbacik
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Schröder
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium / Q000493:pharmacokinetics
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D000068258:Bevacizumab; D015040:Zirconium; D000068878:Trastuzumab