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Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6...

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Autores principales: Sharma, R, Kacevska, M, London, R, Clarke, S J, Liddle, C, Robertson, G
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359691/
https://www.ncbi.nlm.nih.gov/pubmed/18059400
http://dx.doi.org/10.1038/sj.bjc.6604101
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author Sharma, R
Kacevska, M
London, R
Clarke, S J
Liddle, C
Robertson, G
author_facet Sharma, R
Kacevska, M
London, R
Clarke, S J
Liddle, C
Robertson, G
author_sort Sharma, R
collection PubMed
description There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.
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spelling pubmed-23596912009-09-10 Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies Sharma, R Kacevska, M London, R Clarke, S J Liddle, C Robertson, G Br J Cancer Translational Therapeutics There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism. Nature Publishing Group 2008-01-15 2007-12-04 /pmc/articles/PMC2359691/ /pubmed/18059400 http://dx.doi.org/10.1038/sj.bjc.6604101 Text en Copyright © 2008 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits 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 license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license 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 license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Translational Therapeutics
Sharma, R
Kacevska, M
London, R
Clarke, S J
Liddle, C
Robertson, G
Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
title Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
title_full Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
title_fullStr Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
title_full_unstemmed Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
title_short Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
title_sort downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359691/
https://www.ncbi.nlm.nih.gov/pubmed/18059400
http://dx.doi.org/10.1038/sj.bjc.6604101
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