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Significance of Thymidylate Synthase Activity in Renal Cell Carcinoma¹

Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 602-8566 [Y. M., M. Na., T. M.]; Departments of Thoracic Surgery [H. W.] and Urology [O. Y.], Graduate School of Medicine, Faculty of Medicine, Kyoto University, Kyoto 606-8507; Cancer Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama 357-8527 [M. F.]; and Department of Urology, Kyoto Katsura Hospital, Kyoto 615-8256 [M. No.], Japan

Purpose: 5-Fluorouracil (5-FU) is an anticancer 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 dUMP to dTMP in the DNA synthetic process. Little is known about the significance of TS in RCC. We investigated the activity of TS in 68 RCCs and the association with dihydropyrimidine dehydrogenase (DPD) activities, which is a principal enzyme in the degradation of 5-FU and pyrimidine nucleotides. The relationship between TS/DPD activities in primary cultured RCC cell lines and their sensitivity to 5-FU was also examined.

Experimental Design: The levels of TS and DPD activities in nonfixed fresh-frozen RCC and normal kidney were determined biochemically by the 5-fluoro-2'-deoxyuridine 5'-monophosphate binding assay and the 5-FU degradation assay, respectively. The sensitivity of primary cultured RCC cells to 5-FU was assessed by the microculture tetrazolium dye assay.

Results: The activity of TS was 5-fold higher in RCC compared with normal kidney. TS activity in T_3/4 RCC was 2.5-fold higher than that in T_1/2 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 with those with high activity in the 5-year follow-up. There was no relationship between TS and DPD activities. TS activity in primary cultured RCC cells was positively correlated with their sensitivity to 5-FU. Furthermore, RCC cells with both high TS activity and low DPD activity were more sensitive to 5-FU, compared with those with either low TS activity or high DPD activity.

Conclusions: The present study is the first study to demonstrate that the level of TS activity was correlated with both the progression of the stage and the increase of the grade of RCC, and that higher TS activity in primary cultured RCC predicted higher sensitivity to 5-FU. These results suggest that high TS activity may be associated with malignant potential of RCC, and that it may be possible to use 5-FU for RCC with high TS activity.

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