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Prognostic significance of thymidylate synthase activity in bladder carcinoma
1Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. ymizutan@koto.kpu-m.ac.jp
Background:
5-fluorouracil (5-FU) is an anticancer agent clinically used against various cancers including bladder carcinoma. 5-FU inhibits thymidylate synthase (TS) and blocks DNA synthesis. TS is the key enzyme in the catalysis of the methylation from deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate. Little is known about the significance of TS in bladder carcinoma. The authors investigated the activity of TS in 82 bladder cancers and prognostic significance of the levels of TS and/or activities of dihydropyrimidine dehydrogenase (DPD), an important enzyme in the degradation of 5-FU.
Methods:
The levels of TS and DPD activities in nonfixed, fresh, frozen, bladder carcinoma and normal bladder specimens were determined biochemically by the FdUMP binding assay and the 5-FU degradation assay, respectively.
Results:
The activity of TS was 10-fold higher in bladder carcinoma compared with normal bladder. TS activity in muscle-invasive bladder carcinoma was threefold higher than that in Ta and T1 cancer. In addition, the activity of TS in T1 bladder carcinoma was threefold higher than that in Ta cancer. The level of TS activity in Grade 3 bladder carcinoma was 4.5-fold and 3.5-fold higher than that in Grade 1 and Grade 2 cancers, respectively. Patients with Ta and T1 bladder carcinoma with low TS activity had a longer postoperative tumor-free period than those with high activity in the 2-year follow-up. Patients with Ta and T1 bladder carcinoma with high or low TS activity were divided into four subgroups: high or low DPD activity subgroups. Patients with low TS activity and high DPD activity had the longest postoperative disease-free period among the 4 subgroups during the 2-year follow-up.
Conclusions:
To the authors' knowledge, the current study is the first study that demonstrated that the level of TS activity correlates with both the progression of the stage and the increase of the grade of bladder carcinoma and that elevated TS activity predicts early recurrence in Ta and T1 bladder carcinoma. These results suggested that elevated TS activity might have been associated with a higher chance of progression and recurrence of bladder carcinoma in the patients who participated in this study.
Insights
Thymidylate synthase (TS) activity is elevated in bladder carcinoma and correlates with cancer stage and grade. High TS activity predicts early recurrence in early-stage bladder cancers, suggesting its prognostic significance.
Area of Science:
- Oncology
- Biochemistry
Background:
- 5-fluorouracil (5-FU) is a chemotherapy agent targeting thymidylate synthase (TS).
- The role of TS in bladder carcinoma progression and recurrence is not well understood.
- Dihydropyrimidine dehydrogenase (DPD) is crucial for 5-FU metabolism.
Purpose of the Study:
- To investigate TS activity in bladder carcinoma.
- To determine the prognostic significance of TS and DPD in bladder cancer patients.
- To correlate TS levels with tumor stage and grade.
Main Methods:
- Biochemical assays were used to measure TS and DPD activity in bladder cancer and normal tissues.
- FdUMP binding assay for TS activity.
- 5-FU degradation assay for DPD activity.
Main Results:
- TS activity was 10-fold higher in bladder tumors than normal tissue.
- Elevated TS activity correlated with higher tumor stage (muscle-invasive vs. Ta/T1) and grade (Grade 3 vs. 1/2).
- Low TS activity was associated with a longer disease-free period in Ta/T1 tumors; high DPD activity further improved outcomes.
Conclusions:
- TS activity levels correlate with bladder carcinoma stage and grade.
- Elevated TS activity is a predictor of early recurrence in Ta and T1 bladder carcinoma.
- Combined assessment of TS and DPD may offer prognostic value for bladder cancer.