Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake

M. Arjaans, T.H. Oude Munnink, S.F. Oosting, A.G.T. Terwisscha van Scheltinga, J.A. Gietema, E.T. Garbacik, H. Timmer-Bosscha, M. Lub-de Hooge, C.P. Schroder, E.G.E. de Vries

Research output: Contribution to journalArticleAcademicpeer-review

65 Citations (Scopus)

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 89Zr-trastuzumab (SKOV-3 and OE19), 89Zr-bevacizumab (SKOV-3), or 89Zr-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.
Original languageEnglish
Pages (from-to)3347-3355
Number of pages9
JournalCancer research
Volume73
DOIs
Publication statusPublished - 11 Apr 2013

Fingerprint

Vascular Tissue Neoplasms
Neoplasm Antibodies
Neoplasms
Pericytes
Tumor Microenvironment
Antibodies
Capillary Permeability
Therapeutics
Esophageal Neoplasms
Bevacizumab
Fluorescence Microscopy
Heterografts
Pharmaceutical Preparations
Ovarian Neoplasms
Blood Vessels
Drainage
Permeability
Immunoglobulin G
Electrons
Injections

Keywords

  • IR-87308
  • METIS-297894

Cite this

Arjaans, M., Oude Munnink, T. H., Oosting, S. F., Terwisscha van Scheltinga, A. G. T., Gietema, J. A., Garbacik, E. T., ... de Vries, E. G. E. (2013). Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer research, 73, 3347-3355. https://doi.org/10.1158/0008-5472.CAN-12-3518
Arjaans, M. ; Oude Munnink, T.H. ; Oosting, S.F. ; Terwisscha van Scheltinga, A.G.T. ; Gietema, J.A. ; Garbacik, E.T. ; Timmer-Bosscha, H. ; Lub-de Hooge, M. ; Schroder, C.P. ; de Vries, E.G.E. / Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. In: Cancer research. 2013 ; Vol. 73. pp. 3347-3355.
@article{88709b15ceb54affb4a196f7bdfad0af,
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 89Zr-trastuzumab (SKOV-3 and OE19), 89Zr-bevacizumab (SKOV-3), or 89Zr-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.",
keywords = "IR-87308, METIS-297894",
author = "M. Arjaans and {Oude Munnink}, T.H. and S.F. Oosting and {Terwisscha van Scheltinga}, A.G.T. and J.A. Gietema and E.T. Garbacik and H. Timmer-Bosscha and {Lub-de Hooge}, M. and C.P. Schroder and {de Vries}, E.G.E.",
year = "2013",
month = "4",
day = "11",
doi = "10.1158/0008-5472.CAN-12-3518",
language = "English",
volume = "73",
pages = "3347--3355",
journal = "Cancer research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",

}

Arjaans, M, Oude Munnink, TH, Oosting, SF, Terwisscha van Scheltinga, AGT, Gietema, JA, Garbacik, ET, Timmer-Bosscha, H, Lub-de Hooge, M, Schroder, CP & de Vries, EGE 2013, 'Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake' Cancer research, vol. 73, pp. 3347-3355. https://doi.org/10.1158/0008-5472.CAN-12-3518

Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. / Arjaans, M.; Oude Munnink, T.H.; Oosting, S.F.; Terwisscha van Scheltinga, A.G.T.; Gietema, J.A.; Garbacik, E.T.; Timmer-Bosscha, H.; Lub-de Hooge, M.; Schroder, C.P.; de Vries, E.G.E.

In: Cancer research, Vol. 73, 11.04.2013, p. 3347-3355.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake

AU - Arjaans, M.

AU - Oude Munnink, T.H.

AU - Oosting, S.F.

AU - Terwisscha van Scheltinga, A.G.T.

AU - Gietema, J.A.

AU - Garbacik, E.T.

AU - Timmer-Bosscha, H.

AU - Lub-de Hooge, M.

AU - Schroder, C.P.

AU - de Vries, E.G.E.

PY - 2013/4/11

Y1 - 2013/4/11

N2 - 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 89Zr-trastuzumab (SKOV-3 and OE19), 89Zr-bevacizumab (SKOV-3), or 89Zr-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.

AB - 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 89Zr-trastuzumab (SKOV-3 and OE19), 89Zr-bevacizumab (SKOV-3), or 89Zr-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.

KW - IR-87308

KW - METIS-297894

U2 - 10.1158/0008-5472.CAN-12-3518

DO - 10.1158/0008-5472.CAN-12-3518

M3 - Article

VL - 73

SP - 3347

EP - 3355

JO - Cancer research

JF - Cancer research

SN - 0008-5472

ER -

Arjaans M, Oude Munnink TH, Oosting SF, Terwisscha van Scheltinga AGT, Gietema JA, Garbacik ET et al. Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer research. 2013 Apr 11;73:3347-3355. https://doi.org/10.1158/0008-5472.CAN-12-3518