Study on DNA Metabolizing Enzymes as Molecular Theraputic Targets in Renal Cell Carcinoma

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5-fluorouracil(5-FU) is an anticancer chemotherapeutic agent clinically used against various cancers including renal cell carcinoma(RCC). 5-FU inhibits thymidylate synthase(TS) and blocks DNA synthesis. TS is the key enzyme in the catalysis of the methylation from deoxyuridine monophosphate to deoxythymidine monophosphate in the DNA synthetic process. Little is known about the significance of TS in RCC. We investigated the activity of TS in 68 RCC samples and evaluated the association between the level of TS activity and the stage/grade of RCC. In addition, prognostic significance of TS activity in RCC was examined. The relationship between TS activity in primary cultured RCC cell lines and their sensitivity to 5-FU was also analyzed.The level of TS activity in non-fixed fresh frozen RCC and normal kidney specimens was determined biochemically by the 5-fluoro-2'-deoxyuridine 5'-monophosphate binding assay. The sensitivity of primary cultured RCC cell lines to 5-FU was assessed by the m … More icroculture tetrazolium dye assay.The activity of TS was approximately 5-fold higher in RCC compared to normal kidney. TS activity in T3/4 RCC was 2.5-fold higher than that in T1/2 RCC. TS activity in M1 RCC was 2.5-fold higher than that in M0 RCC. In addition, TS activity in Stage III/IV RCC was 3-fold higher than that in Stage I/II RCC. The levels of TS activity in Grade 3 RCC were 3-fold and 2-fold higher than that in Grade 1 and Grade 2 cancer, respectively. TS activity in clear cell RCC were 4-fold higher than that in papillary RCC. Patients with low TS activity had a longer disease-specific survival as compared to those with high activity in the 5-year follow-up. TS activity in primary cultured RCC cell lines positively correlated with their sensitivity to 5-FU.The present study is the first study to demonstrate that TS activity in RCC was higher than that in normal kidney, and that the level of TS activity correlated with both the progression of the stage and the increase of the grade of RCC. In addition, higher TS activity in RCC predicted worse prognosis and higher sensitivity to 5-FU. These results suggest that the level of TS activity may be used as both a prognostic parameter and a predictive indicator for 5-FU efficacy in RCC, and that TS may be a molecular therapeutic target in RCC. Less