Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma
| Autor: | Takeo Kosaka, Hiroki Ide, Norihide Kozakai, Masanori Hasegawa, Akira Miyajima, Eiji Kikuchi, Mototsugu Oya |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Adult
Antimetabolites Antineoplastic Urologic Neoplasms Cancer Research Pathology medicine.medical_specialty Pyridines Thymidylate synthase lcsh:RC254-282 Mice Surgical oncology Cell Line Tumor Genetics medicine Dihydropyrimidine dehydrogenase Animals Humans Clinical significance 5-fluorouracil RNA Small Interfering Dihydrouracil Dehydrogenase (NADP) Aged Aged 80 and over chemistry.chemical_classification Mice Inbred BALB C biology business.industry Drug Synergism S-1 Middle Aged Prognosis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Enzyme Oncology chemistry Fluorouracil Cell culture biology.protein Cancer research Female Urothelial carcinoma Stem cell business Research Article medicine.drug |
| Zdroj: | BMC Cancer, Vol 12, Iss 1, p 420 (2012) BMC Cancer |
| ISSN: | 1471-2407 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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