Abstract 904: Significance of thymidylate synthase (TS), thymidine kinase (TK) and orotate phosphoribosyltransferase (OPRT) activities as biomarkers in bladder cancer
Authors: Yoichi Mizutani, Yu Edagawa, Hiroshi Fujisue, Shinya Uchimoto, Teruo Inamoto, Kiyoshi Takahara, Takanobu Ubai, Hayahito Nomi, Haruhito Azuma, Yoji Katsuoka
Journal: Cancer Research (2011)

Abstract Introduction and Objective : Thymidylate synthase (TS) and thymidine kinase (TK) are the key enzymes in the de novo and salvage DNA synthetic process, respectively. Orotate phosphoribosyltransferase (OPRT) plays a key role in the de novo pathway of DNA and RNA synthesis. Little is known about the significance of TS, TK and OPRT activities in various cancers including bladder cancer. We examined TS, TK and OPRT activities in 82 bladder cancers and normal bladders and evaluated the correlation between the level of the enzymatic activities and the stage/grade status of bladder cancer. In addition, the prognostic significance was also examined in patients with bladder cancer. Methods : TS, TK and OPRT activities in non-fixed fresh frozen bladder cancers and normal bladders were measured biochemically by the FdUMP binding assay, the DEAE cellulose disc method and the 5-FU phosphorylation assay, respectively. Results : TS activity was 10-fold higher in bladder cancer compared to normal bladder. The activity of TS in muscle-invasive bladder cancer was 3-fold higher than that in non-muscle-invasive cancer. In addition, the level of TS activity in Grade 3 bladder cancer was 4.5-fold and 3.5-fold higher than those in Grade 1 and Grade 2 cancers, respectively. TK activity was approximately 2-fold higher in bladder cancer compared with normal bladder. TK activity in muscle-invasive bladder cancer was 2-fold higher than that in non-muscle-invasive bladder cancer. Furthermore, the level of TK activity in Grade 3 bladder cancer was 2-fold higher than those in Grade 1 and Grade 2 cancers. The activity of OPRT was approximately 7.5-fold higher in bladder cancer compared to normal bladder. OPRT activity in muscle-invasive bladder cancer was 2-fold higher than that in non-muscle-invasive bladder cancer. The level of OPRT activity in Grade 3 bladder cancer was 6-fold and 2-fold higher than those in Grade 1 and Grade 2 cancers, respectively. The level of TS activity was associated with the level of TK activity. Moreover, the level of OPRT activity correlated with those of TS and TK activities. High TS, TK and OPRT activities predicted worse prognosis in patients with Ta and T1 non-muscle-invasive bladder cancer. OPRT activity had the strongest relationship between prognosis and the level of activity. Conclusions : The current study has shown that TS, TK and OPRT activities in bladder cancer were higher than that in normal bladder, and that TS, TK and OPRT activities positively correlated with the stage/grade status of bladder cancer. In addition, the levels of TS, TK and OPRT activities were prognostic indicators in patients with bladder cancer. The present study has demonstrated that TS, TK and OPRT activities may be biomarkers in bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 904. doi:10.1158/1538-7445.AM2011-904