The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine

被引:113
作者
Shimma, N
Umeda, I
Arasaki, M
Murasaki, C
Masubuchi, K
Kohchi, Y
Miwa, M
Ura, M
Sawada, N
Tahara, H
Kuruma, I
Horii, I
Ishitsuka, H
机构
[1] Nippon Roche Res Ctr, Dept Chem, Kamakura, Kanagawa 2478530, Japan
[2] Nippon Roche Res Ctr, Dept Oncol, Kamakura, Kanagawa 2478530, Japan
[3] Nippon Roche Res Ctr, Dept Pharmacokinet, Kamakura, Kanagawa 2478530, Japan
[4] Nippon Roche Res Ctr, Dept Toxicol, Kamakura, Kanagawa 2478530, Japan
关键词
D O I
10.1016/S0968-0896(00)00087-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N-4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N-4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluoro-cytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N-4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in turners. When administered orally to monkeys, a derivative having the N-4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys. (C) 2000 Elsevier Science Ltd. All rights reserved.
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页码:1697 / 1706
页数:10
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