Significance of thymidylate synthase activity in renal cell carcinoma.
Significance of thymidylate synthase activity in renal cell carcinoma.
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发表时间：
2003-04
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通讯作者：
Y. Mizutani;H. Wada;O. Yoshida;M. Fukushima;M. Nonomura;M. Nakao;T. Miki
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作者：
Y. Mizutani;H. Wada;O. Yoshida;M. Fukushima;M. Nonomura;M. Nakao;T. Miki
用途 5-氟尿嘧啶 (5-FU) 是一种抗癌剂，临床上用于治疗包括肾细胞癌 (RCC) 在内的多种癌症。 5-FU 抑制胸苷酸合酶 (TS) 并阻断 DNA 合成。 TS是DNA合成过程中催化dUMP甲基化为dTMP的关键酶。人们对 TS 在 RCC 中的重要性知之甚少。我们研究了 68 个 RCC 中 TS 的活性以及与二氢嘧啶脱氢酶 (DPD) 活性的关联，二氢嘧啶脱氢酶是 5-FU 和嘧啶核苷酸降解的主要酶。还检查了原代培养的 RCC 细胞系中 TS/DPD 活性与其对 5-FU 敏感性之间的关系。实验设计分别通过5-氟-2'-脱氧尿苷5'-单磷酸结合测定和5-FU降解测定来生化测定未固定的新鲜冷冻RCC和正常肾脏中的TS和DPD活性水平。通过微量培养四唑染料测定评估原代培养的 RCC 细胞对 5-FU 的敏感性。结果 RCC 中 TS 的活性比正常肾脏高约 5 倍。 T(3/4) RCC 中的 TS 活性比 T(1/2) RCC 中高 2.5 倍。 M(1) RCC 中的 TS 活性比 M(0) RCC 中高 2.5 倍。此外，III/IV期RCC的TS活性比I/II期RCC高3倍。 3级RCC中的TS活性水平分别比1级和2级癌症高3倍和2倍。透明细胞肾细胞癌中的 TS 活性比乳头状肾细胞癌高 4 倍。在 5 年随访中，与 TS 活性高的患者相比，TS 活性低的患者具有更长的疾病特异性生存期。 TS 和 DPD 活动之间没有关系。原代培养的肾细胞癌细胞中的TS活性与其对5-FU的敏感性呈正相关。此外，与具有低TS活性或高DPD活性的RCC细胞相比，具有高TS活性和低DPD活性的RCC细胞对5-FU更敏感。结论 本研究是第一项证明 TS 活性水平与 RCC 分期进展和分级增加相关的研究，并且原代培养 RCC 中较高的 TS 活性预示着对 5-FU 的敏感性较高。这些结果表明，高 TS 活性可能与 RCC 的恶性潜能相关，并且可能使用 5-FU 治疗高 TS 活性的 RCC。
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 approximately 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 M(1) RCC was 2.5-fold higher than that in M(0) 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.