Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H
Nippon Roche Research Centre, Kanagawa, Japan.
Eur J Cancer. 1998 Jul;34(8):1274-81. doi: 10.1016/s0959-8049(98)00058-6.
Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) selectively in tumours through a cascade of three enzymes. The present study investigated tissue localisation of the three enzymes in humans, which was helpful for us to design the compound. Carboxylesterase was almost exclusively located in the liver and hepatoma, but not in other tumours and normal tissue adjacent to the tumours. Cytidine (Cyd) deaminase was located in high concentrations in the liver and various types of solid tumours. Finally, thymidine phosphorylase (dThdPase) was also more concentrated in various types of tumour tissues than in normal tissues. These unique tissue localisation patterns enabled us to design capecitabine. Oral capecitabine would pass intact through the intestinal tract, but would be converted first by carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-dFCyd) in the liver, then by Cyd deaminase to 5'-deoxy-5-fluorouridine (5'-dFUrd) in the liver and tumour tissues and finally by dThdPase to 5-FU in tumours. In cultures of human cancer cell lines, the highest level of cytotoxicity was shown by 5-FU itself, followed by 5'-dFUrd. Capecitabine and 5'-dFCyd had weak cytotoxic activity only at high concentrations. The cytotoxicity of the intermediate metabolites 5'-dFCyd and 5'-dFCyd was suppressed by inhibitors of Cyd deaminase and dThdPase, respectively, indicating that these metabolites become effective only after their conversion to 5-FU. Capecitabine, which is finally converted to 5-FU by dThdPase in tumours, should be much safer and more effective than 5-FU, and this was indeed the case in the HCT116 human colon cancer and the MX-1 breast cancer xenograft models.
卡培他滨（N4-戊氧羰基-5'-脱氧-5-氟胞苷）是一种新型口服氟嘧啶氨基甲酸酯，它通过一系列三种酶在肿瘤中选择性地转化为5-氟尿嘧啶（5-FU）。本研究调查了这三种酶在人体中的组织定位，这有助于我们设计该化合物。羧酸酯酶几乎只存在于肝脏和肝癌中，而不存在于其他肿瘤及肿瘤邻近的正常组织中。胞苷脱氨酶在肝脏和各种实体瘤中高浓度存在。最后，胸苷磷酸化酶（dThdPase）在各种肿瘤组织中的浓度也高于正常组织。这些独特的组织定位模式使我们能够设计卡培他滨。口服卡培他滨可完整通过肠道，但首先会在肝脏中被羧酸酯酶转化为5'-脱氧-5-氟胞苷（5'-dFCyd），然后在肝脏和肿瘤组织中被胞苷脱氨酶转化为5'-脱氧-5-氟尿苷（5'-dFUrd），最后在肿瘤中被dThdPase转化为5-FU。在人癌细胞系培养中，5-FU本身显示出最高水平的细胞毒性，其次是5'-dFUrd。卡培他滨和5'-dFCyd仅在高浓度时具有较弱的细胞毒性。中间代谢产物5'-dFCyd和5'-dFCyd的细胞毒性分别被胞苷脱氨酶和dThdPase的抑制剂所抑制，这表明这些代谢产物只有在转化为5-FU后才变得有效。最终在肿瘤中被dThdPase转化为5-FU的卡培他滨应该比5-FU更安全、更有效，在HCT116人结肠癌和MX-1乳腺癌异种移植模型中确实如此。
