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Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours.
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for degradation of 5-fluorouracil (5-FU). DPD activity is highly variable in liver and peripheral mononuclear cells (PMNCs) and it has not been well studied in human tumours. Characterization of DPD in colorectal cancer is of clinical...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
1998
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151304/ https://www.ncbi.nlm.nih.gov/pubmed/9472644 |
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author | McLeod, H. L. Sludden, J. Murray, G. I. Keenan, R. A. Davidson, A. I. Park, K. Koruth, M. Cassidy, J. |
author_facet | McLeod, H. L. Sludden, J. Murray, G. I. Keenan, R. A. Davidson, A. I. Park, K. Koruth, M. Cassidy, J. |
author_sort | McLeod, H. L. |
collection | PubMed |
description | Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for degradation of 5-fluorouracil (5-FU). DPD activity is highly variable in liver and peripheral mononuclear cells (PMNCs) and it has not been well studied in human tumours. Characterization of DPD in colorectal cancer is of clinical interest through its role in the regulation of 5-FU, the main chemotherapeutic agent used in this disease. Therefore, DPD activity was analysed in colorectal tumour and adjacent normal tissue from 63 patients, including three liver metastasis. DPD activity was highly variable in all tissues studied (coefficient of variation 43-61%) and was higher in normal tissue than in tumour. The tumour-normal activity ratio ranged from 0.19 to 3.32 (median 0.76). PMNC DPD activity was available for 57 patients and was correlated with tumour activity (r(s) = 0.29, P < 0.001). A higher correlation was observed between PMNCs and tumour samples that were both obtained in the morning (r(s) = 0.49), consistent with circadian variation in DPD activity. Normal tissue DPD activity was not correlated with either tumour (r(s) = 0.11) or PMNC activity (r(s) = -0.06). This study provides the first analysis of DPD activity in colorectal cancer and illustrates the large degree of variation in tumour activity. The tumour-normal activity ratio results suggest that elevated tumour DPD can play a role in 5-FU resistance through increased inactivation in tumour cells, but is an uncommon event in colorectal tumours. The results support the use of PMNCs for monitoring tumour DPD activity, particularly when circadian variation is taken into account. As a large degree of the variation in tumour DPD activity is not explained by PMNC activity, more accurate alternatives are needed before DPD activity can be used for targeting 5-FU therapy. |
format | Text |
id | pubmed-2151304 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1998 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-21513042009-09-10 Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. McLeod, H. L. Sludden, J. Murray, G. I. Keenan, R. A. Davidson, A. I. Park, K. Koruth, M. Cassidy, J. Br J Cancer Research Article Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for degradation of 5-fluorouracil (5-FU). DPD activity is highly variable in liver and peripheral mononuclear cells (PMNCs) and it has not been well studied in human tumours. Characterization of DPD in colorectal cancer is of clinical interest through its role in the regulation of 5-FU, the main chemotherapeutic agent used in this disease. Therefore, DPD activity was analysed in colorectal tumour and adjacent normal tissue from 63 patients, including three liver metastasis. DPD activity was highly variable in all tissues studied (coefficient of variation 43-61%) and was higher in normal tissue than in tumour. The tumour-normal activity ratio ranged from 0.19 to 3.32 (median 0.76). PMNC DPD activity was available for 57 patients and was correlated with tumour activity (r(s) = 0.29, P < 0.001). A higher correlation was observed between PMNCs and tumour samples that were both obtained in the morning (r(s) = 0.49), consistent with circadian variation in DPD activity. Normal tissue DPD activity was not correlated with either tumour (r(s) = 0.11) or PMNC activity (r(s) = -0.06). This study provides the first analysis of DPD activity in colorectal cancer and illustrates the large degree of variation in tumour activity. The tumour-normal activity ratio results suggest that elevated tumour DPD can play a role in 5-FU resistance through increased inactivation in tumour cells, but is an uncommon event in colorectal tumours. The results support the use of PMNCs for monitoring tumour DPD activity, particularly when circadian variation is taken into account. As a large degree of the variation in tumour DPD activity is not explained by PMNC activity, more accurate alternatives are needed before DPD activity can be used for targeting 5-FU therapy. Nature Publishing Group 1998 /pmc/articles/PMC2151304/ /pubmed/9472644 Text en 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 | Research Article McLeod, H. L. Sludden, J. Murray, G. I. Keenan, R. A. Davidson, A. I. Park, K. Koruth, M. Cassidy, J. Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
title | Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
title_full | Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
title_fullStr | Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
title_full_unstemmed | Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
title_short | Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
title_sort | characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151304/ https://www.ncbi.nlm.nih.gov/pubmed/9472644 |
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