Format

Send to

Choose Destination
J Nucl Med. 2017 Feb;58(2):214-220. doi: 10.2967/jnumed.116.177741. Epub 2016 Aug 4.

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow.

Author information

1
Laboratory of Pediatric Oncology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
2
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Division of Imaging Sciences and Biomedical Engineering, Department of Imaging Chemistry and Biology, King's College London, London, United Kingdom.
4
Experimental Rheumatology, Radboud Insititute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany.
6
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany.
7
German Cancer Consortium (DKTK), Freiburg, Germany.
8
BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany; and.
9
Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
10
Laboratory of Pediatric Oncology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands FrankN.vanleeuwen@radboudumc.nl.

Abstract

The antileukemic drug asparaginase, a key component in the treatment of acute lymphoblastic leukemia, acts by depleting asparagine from the blood. However, little is known about its pharmacokinetics, and mechanisms of therapy resistance are poorly understood. Here, we explored the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochemical techniques, and provide evidence for tissue-specific clearance mechanisms, which could reduce the effectiveness of the drug at these specific sites.

METHODS:

In vivo localization of 111In-labeled Escherichia coli asparaginase was performed in C57BL/6 mice by both small-animal SPECT/CT and ex vivo biodistribution studies. Mice were treated with liposomal clodronate to investigate the effect of macrophage depletion on tracer localization and drug clearance in vivo. Moreover, macrophage cell line models RAW264.7 and THP-1, as well as knockout mice, were used to identify the cellular and molecular components controlling asparaginase pharmacokinetics.

RESULTS:

In vivo imaging and biodistribution studies showed a rapid accumulation of asparaginase in macrophage-rich tissues such as the liver, spleen, and in particular bone marrow. Clodronate-mediated depletion of phagocytic cells markedly prolonged the serum half-life of asparaginase in vivo and decreased drug uptake in these macrophage-rich organs. Immunohistochemistry and in vitro binding assays confirmed the involvement of macrophagelike cells in the uptake of asparaginase. We identified the activity of the lysosomal protease cathepsin B in macrophages as a rate-limiting factor in degrading asparaginase both in vitro and in vivo.

CONCLUSION:

We showed that asparaginase is rapidly cleared from the serum by liver-, spleen-, and bone marrow-resident phagocytic cells. As a consequence of this efficient uptake and protease-mediated degradation, particularly bone marrow-resident macrophages may provide a protective niche to leukemic cells.

KEYWORDS:

asparaginase; cathepsin B; imaging; leukemia; macrophages

PMID:
27493268
DOI:
10.2967/jnumed.116.177741
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center