著者

河野 彬 原 泰寛 菅田 節朗 加留部 善晴 松島 美一 石塚 秀夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.1, pp.175-178, 1983-01-25 (Released:2008-03-31)

参考文献数

20

被引用文献数

77 93

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Activities of pyrimidine nucleoside phosphorylases were assayed in extracts of human tumors, normal tissues of the same organs and tumors of mice (Sarcoma-180) and guinea pigs (Line-10), with thymidine (dThd), uridine (Urd), and 5'-deoxy-5-fluorouridine (5'-DFUR) as substrates. The nucleoside cleaving activities were higher in extracts of human tumor tissues than in those of normal tissues of the same organs. In human tissues, phosphorolytic activitiy towards dThd was high, while that towards Urd was low. In animal tumors, Urd was the best substrate. 1-(2'-Deoxy-β-D-glucopyranosyl)-thymine (GPT), a specific inhibitor of uridine phosphorylase, inhibited the phosphorolysis of Urd and 5'-DFUR in extracts of animal tumors, but not that of dThd and 5'-DFUR in extracts of human tumors. A thymidine phosphorylase preparation was partialy purified from human lung cancer. Km values of the preparation were 2.43×10-4 M and 1.69×10-3 M for dThd and 5'-DFUR, respectively. We conclude that in human tumors a thymidine phosphorylase activity converts 5'-DFUR to 5-fluorouracil, an activated form.

著者

石塚 秀夫 新間 信夫 堀井 郁夫

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.119, no.12, pp.881-897, 1999-12-01 (Released:2008-05-30)

参考文献数

49

被引用文献数

14 20

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Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three anzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.