Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells
Dihydropyrimidine dehydrogenase (DPD) and pyrimidine nucleoside phosphorylase (PyNPase) are the first and rate‐limiting enzymes that regulate 5‐fluorouracil (5‐FU) metabolism, and tumoral DPD activity appears to be a promising predictor of 5‐FU sensitivity. However, the regulatory mechanisms determi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Blackwell Publishing Ltd
2000
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926278/ https://www.ncbi.nlm.nih.gov/pubmed/11092985 http://dx.doi.org/10.1111/j.1349-7006.2000.tb00903.x |
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author | Ueda, Masatsugu Kitaura, Kozo Kusada, Osamu Mochizuki, Yoshino Yamada, Naomi Terai, Yoshito Kumagai, Koji Ueki, Ken Ueki, Minoru |
author_facet | Ueda, Masatsugu Kitaura, Kozo Kusada, Osamu Mochizuki, Yoshino Yamada, Naomi Terai, Yoshito Kumagai, Koji Ueki, Ken Ueki, Minoru |
author_sort | Ueda, Masatsugu |
collection | PubMed |
description | Dihydropyrimidine dehydrogenase (DPD) and pyrimidine nucleoside phosphorylase (PyNPase) are the first and rate‐limiting enzymes that regulate 5‐fluorouracil (5‐FU) metabolism, and tumoral DPD activity appears to be a promising predictor of 5‐FU sensitivity. However, the regulatory mechanisms determining these enzyme activities have not been fully understood. We investigated the biological effects of epidermal growth factor (EGF) and transforming growth factor (TGF)α on cell growth and tumoral DPD and PyNPase activities, and the subsequent effects on 5‐FU sensitivity in uterine cervical carcinoma SKG‐IIIb cells. The treatment of tumor cells with EGF or TGF‐α resulted in a concentration‐dependent increase in tumor cell growth and PyNPase activity, whereas tumoral DPD activity was inhibited. Their stimulatory effects on tumor cell growth correlated well with PyNPase activity, but were inversely related to DPD activity (P<0.01). 5‐FU sensitivity of tumor cells increased in the presence of EGF or TGF‐α. These growth factors were shown to stimulate the first, rate‐limiting enzyme activity in 5‐FU anabolism and to inhibit that in 5‐FU catabolism, leading to enhancement of the antiproliferative action of 5‐FU at achievable therapeutic levels. The tumor environmental factors, EGF and TGF‐α, may act as intrinsic regulators of DPD and PyNPase activities that affect the 5‐FU sensitivity of individual tumors. |
format | Online Article Text |
id | pubmed-5926278 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2000 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-59262782018-05-11 Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells Ueda, Masatsugu Kitaura, Kozo Kusada, Osamu Mochizuki, Yoshino Yamada, Naomi Terai, Yoshito Kumagai, Koji Ueki, Ken Ueki, Minoru Jpn J Cancer Res Rapid Communication Dihydropyrimidine dehydrogenase (DPD) and pyrimidine nucleoside phosphorylase (PyNPase) are the first and rate‐limiting enzymes that regulate 5‐fluorouracil (5‐FU) metabolism, and tumoral DPD activity appears to be a promising predictor of 5‐FU sensitivity. However, the regulatory mechanisms determining these enzyme activities have not been fully understood. We investigated the biological effects of epidermal growth factor (EGF) and transforming growth factor (TGF)α on cell growth and tumoral DPD and PyNPase activities, and the subsequent effects on 5‐FU sensitivity in uterine cervical carcinoma SKG‐IIIb cells. The treatment of tumor cells with EGF or TGF‐α resulted in a concentration‐dependent increase in tumor cell growth and PyNPase activity, whereas tumoral DPD activity was inhibited. Their stimulatory effects on tumor cell growth correlated well with PyNPase activity, but were inversely related to DPD activity (P<0.01). 5‐FU sensitivity of tumor cells increased in the presence of EGF or TGF‐α. These growth factors were shown to stimulate the first, rate‐limiting enzyme activity in 5‐FU anabolism and to inhibit that in 5‐FU catabolism, leading to enhancement of the antiproliferative action of 5‐FU at achievable therapeutic levels. The tumor environmental factors, EGF and TGF‐α, may act as intrinsic regulators of DPD and PyNPase activities that affect the 5‐FU sensitivity of individual tumors. Blackwell Publishing Ltd 2000-11 /pmc/articles/PMC5926278/ /pubmed/11092985 http://dx.doi.org/10.1111/j.1349-7006.2000.tb00903.x Text en |
spellingShingle | Rapid Communication Ueda, Masatsugu Kitaura, Kozo Kusada, Osamu Mochizuki, Yoshino Yamada, Naomi Terai, Yoshito Kumagai, Koji Ueki, Ken Ueki, Minoru Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells |
title | Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells |
title_full | Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells |
title_fullStr | Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells |
title_full_unstemmed | Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells |
title_short | Regulation of Dihydropyrimidine Dehydrogenase and Pyrimidine Nucleoside Phosphorylase Activities by Growth Factors and Subsequent Effects on 5‐Fluorouracil Sensitivity in Tumor Cells |
title_sort | regulation of dihydropyrimidine dehydrogenase and pyrimidine nucleoside phosphorylase activities by growth factors and subsequent effects on 5‐fluorouracil sensitivity in tumor cells |
topic | Rapid Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926278/ https://www.ncbi.nlm.nih.gov/pubmed/11092985 http://dx.doi.org/10.1111/j.1349-7006.2000.tb00903.x |
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