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Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer

l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase’s anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), resp...

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Autores principales: Horvath, Thomas D., Chan, Wai Kin, Pontikos, Michael A., Martin, Leona A., Du, Di, Tan, Lin, Konopleva, Marina, Weinstein, John N., Lorenzi, Philip L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359345/
https://www.ncbi.nlm.nih.gov/pubmed/30634463
http://dx.doi.org/10.3390/metabo9010010
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author Horvath, Thomas D.
Chan, Wai Kin
Pontikos, Michael A.
Martin, Leona A.
Du, Di
Tan, Lin
Konopleva, Marina
Weinstein, John N.
Lorenzi, Philip L.
author_facet Horvath, Thomas D.
Chan, Wai Kin
Pontikos, Michael A.
Martin, Leona A.
Du, Di
Tan, Lin
Konopleva, Marina
Weinstein, John N.
Lorenzi, Philip L.
author_sort Horvath, Thomas D.
collection PubMed
description l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase’s anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the blood. Unfortunately, accurate assessment of the in vivo pharmacodynamics (PD) of ASNase is challenging because of the following reasons: (i) ASNase is resilient to deactivation; (ii) ASNase catalytic efficiency is very high; and (iii) the PD markers Asn and Gln are depleted ex vivo in blood samples containing ASNase. To address those issues and facilitate longitudinal studies in individual mice for ASNase PD studies, we present here a new LC-MS/MS bioanalytical method that incorporates rapid quenching of ASNase for measurement of Asn, Asp, Gln, and Glu in just 10 µL of whole blood, with limits of detection (s:n ≥ 10:1) estimated to be 2.3, 3.5, 0.8, and 0.5 µM, respectively. We tested the suitability of the method in a 5-day, longitudinal PD study in mice and found the method to be simple to perform with sufficient accuracy and precision for whole blood measurements. Overall, the method increases the density of data that can be acquired from a single animal and will facilitate optimization of novel ASNase treatment regimens and/or the development of new ASNase variants with desired kinetic properties.
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spelling pubmed-63593452019-02-11 Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer Horvath, Thomas D. Chan, Wai Kin Pontikos, Michael A. Martin, Leona A. Du, Di Tan, Lin Konopleva, Marina Weinstein, John N. Lorenzi, Philip L. Metabolites Article l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase’s anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the blood. Unfortunately, accurate assessment of the in vivo pharmacodynamics (PD) of ASNase is challenging because of the following reasons: (i) ASNase is resilient to deactivation; (ii) ASNase catalytic efficiency is very high; and (iii) the PD markers Asn and Gln are depleted ex vivo in blood samples containing ASNase. To address those issues and facilitate longitudinal studies in individual mice for ASNase PD studies, we present here a new LC-MS/MS bioanalytical method that incorporates rapid quenching of ASNase for measurement of Asn, Asp, Gln, and Glu in just 10 µL of whole blood, with limits of detection (s:n ≥ 10:1) estimated to be 2.3, 3.5, 0.8, and 0.5 µM, respectively. We tested the suitability of the method in a 5-day, longitudinal PD study in mice and found the method to be simple to perform with sufficient accuracy and precision for whole blood measurements. Overall, the method increases the density of data that can be acquired from a single animal and will facilitate optimization of novel ASNase treatment regimens and/or the development of new ASNase variants with desired kinetic properties. MDPI 2019-01-09 /pmc/articles/PMC6359345/ /pubmed/30634463 http://dx.doi.org/10.3390/metabo9010010 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Horvath, Thomas D.
Chan, Wai Kin
Pontikos, Michael A.
Martin, Leona A.
Du, Di
Tan, Lin
Konopleva, Marina
Weinstein, John N.
Lorenzi, Philip L.
Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
title Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
title_full Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
title_fullStr Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
title_full_unstemmed Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
title_short Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer
title_sort assessment of l-asparaginase pharmacodynamics in mouse models of cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359345/
https://www.ncbi.nlm.nih.gov/pubmed/30634463
http://dx.doi.org/10.3390/metabo9010010
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