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Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells

Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatme...

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Autores principales: Wakasa, Kentaro, Kawabata, Rumi, Nakao, Seiki, Hattori, Hiroyoshi, Taguchi, Kenichi, Uchida, Junji, Yamanaka, Takeharu, Maehara, Yoshihiko, Fukushima, Masakazu, Oda, Shinya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400010/
https://www.ncbi.nlm.nih.gov/pubmed/25881233
http://dx.doi.org/10.1371/journal.pone.0123076
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author Wakasa, Kentaro
Kawabata, Rumi
Nakao, Seiki
Hattori, Hiroyoshi
Taguchi, Kenichi
Uchida, Junji
Yamanaka, Takeharu
Maehara, Yoshihiko
Fukushima, Masakazu
Oda, Shinya
author_facet Wakasa, Kentaro
Kawabata, Rumi
Nakao, Seiki
Hattori, Hiroyoshi
Taguchi, Kenichi
Uchida, Junji
Yamanaka, Takeharu
Maehara, Yoshihiko
Fukushima, Masakazu
Oda, Shinya
author_sort Wakasa, Kentaro
collection PubMed
description Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy.
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spelling pubmed-44000102015-04-21 Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells Wakasa, Kentaro Kawabata, Rumi Nakao, Seiki Hattori, Hiroyoshi Taguchi, Kenichi Uchida, Junji Yamanaka, Takeharu Maehara, Yoshihiko Fukushima, Masakazu Oda, Shinya PLoS One Research Article Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy. Public Library of Science 2015-04-16 /pmc/articles/PMC4400010/ /pubmed/25881233 http://dx.doi.org/10.1371/journal.pone.0123076 Text en © 2015 Wakasa et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wakasa, Kentaro
Kawabata, Rumi
Nakao, Seiki
Hattori, Hiroyoshi
Taguchi, Kenichi
Uchida, Junji
Yamanaka, Takeharu
Maehara, Yoshihiko
Fukushima, Masakazu
Oda, Shinya
Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
title Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
title_full Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
title_fullStr Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
title_full_unstemmed Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
title_short Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
title_sort dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400010/
https://www.ncbi.nlm.nih.gov/pubmed/25881233
http://dx.doi.org/10.1371/journal.pone.0123076
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