Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue
Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue
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DOI：
10.1016/s0959-8049(98)00058-6
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发表时间：
1998-07-01
影响因子：
8.4
通讯作者：
Ishitsuka, H
中科院分区：
文献类型：
--
作者：
Miwa, M;Ura, M;Ishitsuka, H
卡培他滨（Capecitabine，N-4-pentyloxy carbonyl-5 '-deoxy-5-fluorocytidine）是一种新型的口服氟尿嘧啶氨基甲酸酯，其在肿瘤中通过三种酶的级联反应选择性地转化为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，这有助于我们设计化合物。羧酸酯酶几乎完全位于肝脏和肝癌，但不存在于其他肿瘤和肿瘤附近的正常组织。胞苷（Cyd）脱氨酶在肝脏和各种类型的实体瘤中浓度较高。最后，胸苷磷酸化酶（dThdurase）也更集中在各种类型的肿瘤组织比正常组织。这些独特的组织定位模式使我们能够设计卡培他滨。口服卡培他滨将完整地通过肠道，但首先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Cyd脱氨酶转化为5 '-脱氧-5-氟尿苷（5'-dFUrd），最后在肿瘤中被dThdurine转化为5-FU。在人癌细胞系的培养物中，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仅在高浓度下具有弱的细胞毒活性。中间代谢物5 '-dFCyd和5'-dFUrd的细胞毒性分别被Cyd脱氨酶和dThdurd的抑制剂抑制，表明这些代谢物仅在转化为5-FU后才有效。卡培他滨在肿瘤中最终被dThdlutamine转化为5-FU，应该比5-FU更安全和更有效，在HCT 116人结肠癌和MX-1乳腺癌异种移植模型中确实如此。(C)1998爱思唯尔科技有限公司版权所有。
Capecitabine (N-4-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'-dFUrd 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. (C) 1998 Elsevier Science Ltd. All rights reserved.