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The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition
Thymidylate synthase (TS) is an important enzyme catalysing the reductive methylation of dUMP to dTMP that is further metabolized to dTTP for DNA synthesis. Loss of viability following TS inhibition occurs as a consequence of depleted dTTP pools and at least in some cell lines, accumulation of dUTP...
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2001
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364072/ https://www.ncbi.nlm.nih.gov/pubmed/11487279 http://dx.doi.org/10.1054/bjoc.2001.1921 |
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author | Webley, S D Welsh, S J Jackman, A L Aherne, G W |
author_facet | Webley, S D Welsh, S J Jackman, A L Aherne, G W |
author_sort | Webley, S D |
collection | PubMed |
description | Thymidylate synthase (TS) is an important enzyme catalysing the reductive methylation of dUMP to dTMP that is further metabolized to dTTP for DNA synthesis. Loss of viability following TS inhibition occurs as a consequence of depleted dTTP pools and at least in some cell lines, accumulation of dUTP and subsequent misincorporation of uracil into DNA. The expansion in dUTP pools is largely determined by the expression of the pyrophosphatase, dUTPase. Our previous work has shown that following TS inhibition the ability to accumulate dUTP was associated with an earlier growth inhibitory effect. 3 human lung tumour cell lines and HT29 human colon tumour cells transfected with dUTPase have been used to investigate the relationship between loss of viability following TS inhibition and dUTP accumulation. Cell cycle arrest typical of TS inhibition was an early event in all cell lines and occurred irrespective of the ability to accumulate dUTP or p53 function. However, a large expansion of dUTP pools was associated with mature DNA damage (4 h) and an earlier loss of viability following TS inhibition compared to cells in which dUTP pools were not expanded. In A549 cells damage to mature DNA may have been exacerbated by significantly higher activity of the excision repair enzyme, uracil-DNA glycosylase. Consistent with results using different inhibitors of TS, transfection of dUTPase into HT29 cells significantly reduced the cytotoxicity of a 24 h but not 48 h exposure to ZD9331. Although loss of viability can be mediated through dTTP deprivation alone, the uracil misincorporation pathway resulted in an earlier commitment to cell death. The relevance of this latter pathway in the clinical response to TS inhibitors deserves further investigation. © 2001 Cancer Research Campaign http://www.bjcancer.com |
format | Text |
id | pubmed-2364072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2001 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-23640722009-09-10 The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition Webley, S D Welsh, S J Jackman, A L Aherne, G W Br J Cancer Regular Article Thymidylate synthase (TS) is an important enzyme catalysing the reductive methylation of dUMP to dTMP that is further metabolized to dTTP for DNA synthesis. Loss of viability following TS inhibition occurs as a consequence of depleted dTTP pools and at least in some cell lines, accumulation of dUTP and subsequent misincorporation of uracil into DNA. The expansion in dUTP pools is largely determined by the expression of the pyrophosphatase, dUTPase. Our previous work has shown that following TS inhibition the ability to accumulate dUTP was associated with an earlier growth inhibitory effect. 3 human lung tumour cell lines and HT29 human colon tumour cells transfected with dUTPase have been used to investigate the relationship between loss of viability following TS inhibition and dUTP accumulation. Cell cycle arrest typical of TS inhibition was an early event in all cell lines and occurred irrespective of the ability to accumulate dUTP or p53 function. However, a large expansion of dUTP pools was associated with mature DNA damage (4 h) and an earlier loss of viability following TS inhibition compared to cells in which dUTP pools were not expanded. In A549 cells damage to mature DNA may have been exacerbated by significantly higher activity of the excision repair enzyme, uracil-DNA glycosylase. Consistent with results using different inhibitors of TS, transfection of dUTPase into HT29 cells significantly reduced the cytotoxicity of a 24 h but not 48 h exposure to ZD9331. Although loss of viability can be mediated through dTTP deprivation alone, the uracil misincorporation pathway resulted in an earlier commitment to cell death. The relevance of this latter pathway in the clinical response to TS inhibitors deserves further investigation. © 2001 Cancer Research Campaign http://www.bjcancer.com Nature Publishing Group 2001-08 /pmc/articles/PMC2364072/ /pubmed/11487279 http://dx.doi.org/10.1054/bjoc.2001.1921 Text en Copyright © 2001 Cancer Research Campaign 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 | Regular Article Webley, S D Welsh, S J Jackman, A L Aherne, G W The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition |
title | The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition |
title_full | The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition |
title_fullStr | The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition |
title_full_unstemmed | The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition |
title_short | The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition |
title_sort | ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (ts) inhibition |
topic | Regular Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364072/ https://www.ncbi.nlm.nih.gov/pubmed/11487279 http://dx.doi.org/10.1054/bjoc.2001.1921 |
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