Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma

Hiroki Ide, Eiji Kikuchi, Masanori Hasegawa, Norihide Kozakai, Takeo Kosaka, Akira Miyajima, Mototsugu Oya

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Recently, S-1, a novel 5-fluorouracil (5-FU)-based agent containing the strong dihydropyrimidine dehydrogenase (DPD) inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP) has been clinically used to treat various non-urothelial carcinomas (UC). High levels of thymidylate synthase (TS), the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC) and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model.Methods: Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA) specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model.Results: Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD.Conclusions: TS plays an important role in the prognosis of UTUC and S-1 may be a key agent for UC tumor, especially with a high level of DPD.

Original languageEnglish
Article number420
JournalBMC Cancer
Volume12
DOIs
Publication statusPublished - 2012 Sep 22

Fingerprint

Dihydrouracil Dehydrogenase (NADP)
Thymidylate Synthase
Fluorouracil
Carcinoma
Enzymes
Heterografts
Neoplasms
pyridine
Small Interfering RNA
Tegafur
Cell Line
Tumor Cell Line

Keywords

  • 5-fluorouracil
  • Dihydropyrimidine dehydrogenase
  • S-1
  • Thymidylate synthase
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma. / Ide, Hiroki; Kikuchi, Eiji; Hasegawa, Masanori; Kozakai, Norihide; Kosaka, Takeo; Miyajima, Akira; Oya, Mototsugu.

In: BMC Cancer, Vol. 12, 420, 22.09.2012.

Research output: Contribution to journalArticle

@article{5bc9d1df30ab4b10b933a8bf1b5dfd0f,
title = "Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma",
abstract = "Background: Recently, S-1, a novel 5-fluorouracil (5-FU)-based agent containing the strong dihydropyrimidine dehydrogenase (DPD) inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP) has been clinically used to treat various non-urothelial carcinomas (UC). High levels of thymidylate synthase (TS), the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC) and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model.Methods: Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA) specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model.Results: Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD.Conclusions: TS plays an important role in the prognosis of UTUC and S-1 may be a key agent for UC tumor, especially with a high level of DPD.",
keywords = "5-fluorouracil, Dihydropyrimidine dehydrogenase, S-1, Thymidylate synthase, Urothelial carcinoma",
author = "Hiroki Ide and Eiji Kikuchi and Masanori Hasegawa and Norihide Kozakai and Takeo Kosaka and Akira Miyajima and Mototsugu Oya",
year = "2012",
month = "9",
day = "22",
doi = "10.1186/1471-2407-12-420",
language = "English",
volume = "12",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma

AU - Ide, Hiroki

AU - Kikuchi, Eiji

AU - Hasegawa, Masanori

AU - Kozakai, Norihide

AU - Kosaka, Takeo

AU - Miyajima, Akira

AU - Oya, Mototsugu

PY - 2012/9/22

Y1 - 2012/9/22

N2 - Background: Recently, S-1, a novel 5-fluorouracil (5-FU)-based agent containing the strong dihydropyrimidine dehydrogenase (DPD) inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP) has been clinically used to treat various non-urothelial carcinomas (UC). High levels of thymidylate synthase (TS), the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC) and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model.Methods: Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA) specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model.Results: Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD.Conclusions: TS plays an important role in the prognosis of UTUC and S-1 may be a key agent for UC tumor, especially with a high level of DPD.

AB - Background: Recently, S-1, a novel 5-fluorouracil (5-FU)-based agent containing the strong dihydropyrimidine dehydrogenase (DPD) inhibitor, 5-chloro-2,4-dihydropyrimidine (CDHP) has been clinically used to treat various non-urothelial carcinomas (UC). High levels of thymidylate synthase (TS), the target enzyme of 5-FU and DPD which degrades the majority of 5-FU, are associated with poor prognosis in some cancers. However, only a few reports have dealt with this in UC. The aim of this study was to investigate the clinical significance of TS and DPD in upper tract urothelial carcinoma (UTUC) and evaluate the role of TS and DPD on the sensitivity of 5-FU in UC cell lines and the anti-tumor effect of S-1 in UC xenograft model.Methods: Firstly, we evaluated the immunohistochemical expression of TS and DPD in 176 patients with UTUC to determine their prognostic significance. Secondly, the levels of TS and DPD in UC cell lines were measured by ELISA and real-time PCR. Furthermore, the association between their levels and the sensitivity to 5-FU was examined using the small interfering RNA (siRNA) specific for TS and DPD. Thirdly, the anti-tumor effect of S-1 was evaluated in UC xenograft model.Results: Immunohistochemical evaluation of TS and DPD in UTUC human samples revealed that TS expression was significantly associated with stage, grade, and lymphovascular invasion and DPD expression was significantly associated with grade. Multivariate analysis revealed that high TS expression was an independent predictor of disease-specific survival in them. In in vitro study using UC cell lines, high levels of TS and DPD were associated with low response to 5-FU and these associations were confirmed with siRNA specific for TS and DPD. In in vivo study using UC xenograft model, S-1 treatment dramatically inhibited tumor growth compared to controls, tegafur, or UFT in UC tumor with a high level of DPD.Conclusions: TS plays an important role in the prognosis of UTUC and S-1 may be a key agent for UC tumor, especially with a high level of DPD.

KW - 5-fluorouracil

KW - Dihydropyrimidine dehydrogenase

KW - S-1

KW - Thymidylate synthase

KW - Urothelial carcinoma

UR - http://www.scopus.com/inward/record.url?scp=84866521672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866521672&partnerID=8YFLogxK

U2 - 10.1186/1471-2407-12-420

DO - 10.1186/1471-2407-12-420

M3 - Article

VL - 12

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

M1 - 420

ER -