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5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming

BACKGROUND: Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was...

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Autores principales: Kuehl, Philip J., Tellez, Carmen S., Grimes, Marcie J., March, Thomas H., Tessema, Mathewos, Revelli, David A., Mallis, Larry M., Dye, Wendy W., Sniegowski, Tyler, Badenoch, Aaron, Burke, Michael, Dubose, Devon, Vodak, David T., Picchi, Maria A., Belinsky, Steven A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156464/
https://www.ncbi.nlm.nih.gov/pubmed/32103148
http://dx.doi.org/10.1038/s41416-020-0765-2
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author Kuehl, Philip J.
Tellez, Carmen S.
Grimes, Marcie J.
March, Thomas H.
Tessema, Mathewos
Revelli, David A.
Mallis, Larry M.
Dye, Wendy W.
Sniegowski, Tyler
Badenoch, Aaron
Burke, Michael
Dubose, Devon
Vodak, David T.
Picchi, Maria A.
Belinsky, Steven A.
author_facet Kuehl, Philip J.
Tellez, Carmen S.
Grimes, Marcie J.
March, Thomas H.
Tessema, Mathewos
Revelli, David A.
Mallis, Larry M.
Dye, Wendy W.
Sniegowski, Tyler
Badenoch, Aaron
Burke, Michael
Dubose, Devon
Vodak, David T.
Picchi, Maria A.
Belinsky, Steven A.
author_sort Kuehl, Philip J.
collection PubMed
description BACKGROUND: Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed. METHODS: Pharmacokinetics of inhaled dry powder and aqueous formulations of 5AZA were compared to an injected formulation. Efficacy studies and effect of therapy on the epigenome were conducted in an orthotopic rat lung cancer model for inhaled formulations. RESULTS: Inhaled dry powder 5AZA showed superior pharmacokinetic properties in lung, liver, brain and blood compared to the injected formulation and for all tissues except lung compared to an inhaled aqueous formulation. Only dry powder 5AZA was detected in brain (~4-h half-life). Inhaled dry powder was superior to inhaled aqueous 5AZA in reducing tumour burden 70–95%. Superiority of inhaled 5AZA dry powder was linked to effectively reprogramming the cancer genome through demethylation and gene expression changes in cancer signalling and immune pathways. CONCLUSIONS: These findings could lead to widespread use of this drug as the first inhaled dry powder therapeutic for treating local and metastatic lung cancer, for adjuvant therapy, and in combination with immunotherapy to improve patient survival.
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spelling pubmed-71564642021-02-27 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming Kuehl, Philip J. Tellez, Carmen S. Grimes, Marcie J. March, Thomas H. Tessema, Mathewos Revelli, David A. Mallis, Larry M. Dye, Wendy W. Sniegowski, Tyler Badenoch, Aaron Burke, Michael Dubose, Devon Vodak, David T. Picchi, Maria A. Belinsky, Steven A. Br J Cancer Article BACKGROUND: Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed. METHODS: Pharmacokinetics of inhaled dry powder and aqueous formulations of 5AZA were compared to an injected formulation. Efficacy studies and effect of therapy on the epigenome were conducted in an orthotopic rat lung cancer model for inhaled formulations. RESULTS: Inhaled dry powder 5AZA showed superior pharmacokinetic properties in lung, liver, brain and blood compared to the injected formulation and for all tissues except lung compared to an inhaled aqueous formulation. Only dry powder 5AZA was detected in brain (~4-h half-life). Inhaled dry powder was superior to inhaled aqueous 5AZA in reducing tumour burden 70–95%. Superiority of inhaled 5AZA dry powder was linked to effectively reprogramming the cancer genome through demethylation and gene expression changes in cancer signalling and immune pathways. CONCLUSIONS: These findings could lead to widespread use of this drug as the first inhaled dry powder therapeutic for treating local and metastatic lung cancer, for adjuvant therapy, and in combination with immunotherapy to improve patient survival. Nature Publishing Group UK 2020-02-27 2020-04-14 /pmc/articles/PMC7156464/ /pubmed/32103148 http://dx.doi.org/10.1038/s41416-020-0765-2 Text en © The Author(s), under exclusive licence to Cancer Research UK 2020 https://creativecommons.org/licenses/by/4.0/Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Kuehl, Philip J.
Tellez, Carmen S.
Grimes, Marcie J.
March, Thomas H.
Tessema, Mathewos
Revelli, David A.
Mallis, Larry M.
Dye, Wendy W.
Sniegowski, Tyler
Badenoch, Aaron
Burke, Michael
Dubose, Devon
Vodak, David T.
Picchi, Maria A.
Belinsky, Steven A.
5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
title 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
title_full 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
title_fullStr 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
title_full_unstemmed 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
title_short 5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
title_sort 5-azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156464/
https://www.ncbi.nlm.nih.gov/pubmed/32103148
http://dx.doi.org/10.1038/s41416-020-0765-2
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