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.
authors.affiliation: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ide
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Norihide
authors.initials: N
authors.lastname: Kozakai
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology
chemical_list: C417063:5-chlorodihydroxypyridine; D000964:Antimetabolites, Antineoplastic; D011725:Pyridines; D034741:RNA, Small Interfering; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil