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Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

BACKGROUND: DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions...

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Autores principales: Ramsey, Haley E., Oganesian, Aram, Gorska, Agnieszka E., Fuller, Londa, Arrate, Maria, Boyd, Kelli, Keer, Harold, Azab, Mohammad, Savona, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182630/
https://www.ncbi.nlm.nih.gov/pubmed/32222953
http://dx.doi.org/10.1007/s11523-020-00709-x
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author Ramsey, Haley E.
Oganesian, Aram
Gorska, Agnieszka E.
Fuller, Londa
Arrate, Maria
Boyd, Kelli
Keer, Harold
Azab, Mohammad
Savona, Michael R.
author_facet Ramsey, Haley E.
Oganesian, Aram
Gorska, Agnieszka E.
Fuller, Londa
Arrate, Maria
Boyd, Kelli
Keer, Harold
Azab, Mohammad
Savona, Michael R.
author_sort Ramsey, Haley E.
collection PubMed
description BACKGROUND: DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5–7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients. OBJECTIVE: To determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model. METHODS: Following pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model. RESULTS: Parenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models. CONCLUSIONS: We conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases.
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spelling pubmed-71826302020-04-29 Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model Ramsey, Haley E. Oganesian, Aram Gorska, Agnieszka E. Fuller, Londa Arrate, Maria Boyd, Kelli Keer, Harold Azab, Mohammad Savona, Michael R. Target Oncol Original Research Article BACKGROUND: DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5–7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients. OBJECTIVE: To determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model. METHODS: Following pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model. RESULTS: Parenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models. CONCLUSIONS: We conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases. Springer International Publishing 2020-03-28 2020 /pmc/articles/PMC7182630/ /pubmed/32222953 http://dx.doi.org/10.1007/s11523-020-00709-x Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Original Research Article
Ramsey, Haley E.
Oganesian, Aram
Gorska, Agnieszka E.
Fuller, Londa
Arrate, Maria
Boyd, Kelli
Keer, Harold
Azab, Mohammad
Savona, Michael R.
Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model
title Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model
title_full Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model
title_fullStr Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model
title_full_unstemmed Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model
title_short Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model
title_sort oral azacitidine and cedazuridine approximate parenteral azacitidine efficacy in murine model
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182630/
https://www.ncbi.nlm.nih.gov/pubmed/32222953
http://dx.doi.org/10.1007/s11523-020-00709-x
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