Thymidylate synthase (TS), a key enzyme in DNA synthesis, is over-expressed in a variety of cancer cells. 5-Fluorouracil, an anticancer agent clinically used against various cancers, including prostate cancer, inhibits DNA synthesis by binding TS. In this study, we investigated expression of TS in prostate cancer and its prognostic significance. Seventy-five prostatic tissue specimens were obtained from patients who had undergone prostate biopsy for diagnosis of prostate cancer. We analyzed the cancerous tissue specimens for TS expression using immunohistochemistry. TS expression was significantly increased in patients with bone metastasis. No relationship was found between expression of TS and the other clinicopathological findings. Because TS expression could be used as a prognostic parameter in patients with prostate cancer, an accurate prediction of prognosis might help to select patients for more intensive surgical, hormonal, or chemotherapeutic approaches, including 5-fluorouracil. Additional prospective studies are warranted to define the role of TS in selecting patients for adjuvant therapy for prostate cancer.

1.
Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M: Development of a novel form of 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor-selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548-557.
2.
Tatsumi K, Fukushima M, Shirasaka T, Fujii S: Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extract. Jpn J Cancer Res 1987;78:748-755.
3.
Sakamoto J, Hamada C, Kodaira S, Nakazato H, Ohashi Y: Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patients data meta-analysis of randomized trials. Jpn J Clin Oncol 1999;29:78-86.
4.
Shirasaka T, Shimamoto Y, Fukushima M: Inhibition of oxonic acid on gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 1993;53:4004-4009.
5.
Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A, Saito H, Okabe H, Oyama K, Takeda S, Unemi N, Fukushima M: Antitumor effect of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 1996;56:2602-2606.
6.
Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T: Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 1998;34:1715-1720.
7.
Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, Taguchi T: Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma. Br J Cancer 2000;83:141-145.
8.
Kawahara M, Furuse K, Segawa Y, Yoshimori K, Matsui K, Kudoh S, Hasegawa K, Niitani H, S-1 Cooperative Study Group (Lung Cancer Working Group): Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer. Br J Cancer 2001;85:939-943.
9.
Burdelski C, Strauss C, Tsourlakis MC, Kluth M, Hube-Magg C, Melling N, Lebok P, Minner S, Koop C, Graefen M, Heinzer H, Wittmer C, Krech T, Sauter G, Wilczak W, Simon R, Schlomm T, Steurer S: Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer. Oncotarget 2015;6:8377-8387.
10.
Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, Ishitsuka H: Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998;58:685-690.
11.
Rahman L, Voeller D, Rahman M, Lipkowitz S, Allegra C, Barrett JC, Kaye FJ, Zajac-Kaye M: Thymidylate synthase as an oncogene: a novel role for anessential DNA synthesis enzyme. Cancer Cell 2004;5:341-351.
12.
Li Y, Mizutani Y, Shiraishi T, Okihara K, Ukimura O, Kawauchi A, Nonomura N, Fukushima M, Sakai T, Miki T: Prognostic significance of thymidylate synthase expression in patients with prostate cancer undergoing radical prostatectomy. Urology 2007;69:988-995.
13.
Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S: Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep 2010;23:1345-1350.
14.
Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, Leichman L: Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 1995;55:1407-1412.
15.
Chu E, Koeller DM, Casey JL, Drake JC, Chabner BA, Elwood PC, Zinn S, Allegra CJ: Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci USA 1991;88:8977-8981.
16.
Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ: Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001;1:65-70.
17.
Miyoshi Y, Uemura H, Ishiguro H, Kitamura H, Nomura N, Danenberg PV, Kubota Y: Expression of thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyl transferase in prostate cancer. Prostate Cancer Prostatic Dis 2005;8:260-265.
18.
Kaira K, Okumura T, Ohde Y, Takahashi T, Murakami H, Kondo H, Nakajima T, Yamamoto N: Prognostic significance of thymidylate synthase expression in the adjuvant chemotherapy after resection for pulmonary metastases from colorectal cancer. Anticancer Res 2011;31:2763-2771.
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