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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ueda, Masatsugu, Kitaura, Kozo, Kusada, Osamu, Mochizuki, Yoshino, Yamada, Naomi, Terai, Yoshito, Kumagai, Koji, Ueki, Ken, Ueki, Minoru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2000
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
_version_ 1783318868917223424
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
work_keys_str_mv AT uedamasatsugu regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT kitaurakozo regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT kusadaosamu regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT mochizukiyoshino regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT yamadanaomi regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT teraiyoshito regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT kumagaikoji regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT uekiken regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells
AT uekiminoru regulationofdihydropyrimidinedehydrogenaseandpyrimidinenucleosidephosphorylaseactivitiesbygrowthfactorsandsubsequenteffectson5fluorouracilsensitivityintumorcells