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EJNMMI Research
Published in: EJNMMI Research 1/2019

Open Access 01-12-2019 | Breast Cancer | Original research

Assessment of brain delivery of a model ABCB1/ABCG2 substrate in patients with non-contrast-enhancing brain tumors with positron emission tomography

Authors: Beatrix Wulkersdorfer, Martin Bauer, Rudolf Karch, Harald Stefanits, Cécile Philippe, Maria Weber, Thomas Czech, Marie-Claude Menet, Xavier Declèves, Johannes A. Hainfellner, Matthias Preusser, Marcus Hacker, Markus Zeitlinger, Markus Müller, Oliver Langer

Published in: EJNMMI Research | Issue 1/2019

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Abstract

Background

P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood–brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood–brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors.

Materials and methods

We performed positron emission tomography imaging with the radiolabeled ABCB1 inhibitor [11C]tariquidar, a prototypical ABCB1/ABCG2 substrate, in seven patients with non-contrast -enhancing brain tumors (WHO grades I–III). In addition, ABCB1 and ABCG2 levels were determined in surgically resected tumor tissue of four patients using quantitative targeted absolute proteomics.

Results

Brain distribution of [11C]tariquidar was found to be very low across the whole brain and not significantly different between tumor and tumor-free brain tissue. Only one patient showed a small area of enhanced [11C]tariquidar uptake within the brain tumor. ABCG2/ABCB1 ratios in surgically resected tumor tissue (1.4 ± 0.2) were comparable to previously reported ABCG2/ABCB1 ratios in isolated human micro-vessels (1.3), which suggested that no overexpression of ABCB1 or ABCG2 occurred in the investigated tumors.

Conclusions

Our data suggest that the investigated brain tumors had an intact BBTB, which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates. Therefore, effective drugs for antitumor treatment should have high passive permeability and lack ABCB1/ABCG2 substrate affinity.

Trial registration

European Union Drug Regulating Authorities Clinical Trials Database (EUDRACT), 2011-004189-13. Registered on 23 February 2012, https://​www.​clinicaltrialsre​gister.​eu/​ctr-search/​search?​query=​2011-004189-13.
Appendix
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Metadata
Title
Assessment of brain delivery of a model ABCB1/ABCG2 substrate in patients with non-contrast-enhancing brain tumors with positron emission tomography
Authors
Beatrix Wulkersdorfer
Martin Bauer
Rudolf Karch
Harald Stefanits
Cécile Philippe
Maria Weber
Thomas Czech
Marie-Claude Menet
Xavier Declèves
Johannes A. Hainfellner
Matthias Preusser
Marcus Hacker
Markus Zeitlinger
Markus Müller
Oliver Langer
Publication date
01-12-2019
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2019
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-019-0581-y

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