Ishitsuka H, Shimma N, Horii I
Nippon Roche Research Center, Nippon Roche K. K., Kamakura, Japan.
Yakugaku Zasshi. 1999 Dec;119(12):881-97. doi: 10.1248/yakushi1947.119.12_881.
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 enzymes. 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.
卡培他滨（N4-戊氧基羰基-5'-脱氧-5-氟胞苷）是一种新型口服氟嘧啶氨基甲酸酯，其设计目的是通过肝脏和肿瘤中的三种酶依次转化为5-氟尿嘧啶（5-FU）。包括卡培他滨在内的N4-烷氧基羰基-5'-脱氧-5-氟胞苷衍生物完整地通过肠道，并通过这三种酶的级联反应依次转化为5-FU。第一步是由肝脏中的羧酸酯酶转化为5'-脱氧-5-氟胞苷（5'-DFCR），然后由在肝脏和各种实体瘤中高表达的胞苷脱氨酶转化为5'-脱氧-5-氟尿苷（5'-DFUR），最后由优先存在于肿瘤组织中的胸苷磷酸化酶（dThdPase）转化为5-FU。在大量衍生物中，卡培他滨是根据其对肝脏羧酸酯酶的敏感性、在猴子中的口服生物利用度以及在人癌异种移植模型中的疗效而选定的。口服卡培他滨在肿瘤内产生的5-FU浓度显著高于血浆或正常组织（肌肉）中的浓度。肿瘤中的5-FU水平也远高于等毒性剂量腹腔注射5-FU所达到的水平。这种5-FU的肿瘤选择性递送确保了比其他氟嘧啶更高的疗效和更良好的安全性。在研究的24种人癌异种移植模型中，卡培他滨在更宽的剂量范围内比5-FU、优福定或其中间代谢物5'-DFUR更有效，且具有更广泛的抗肿瘤活性谱。异种移植瘤对卡培他滨的敏感性与肿瘤dThdPase水平相关。此外，在对卡培他滨难治的异种移植模型中，肿瘤中dThdPase将5'-DFUR转化为5-FU的效率不足。此外，卡培他滨的疗效可通过dThdPase上调剂增强，如紫杉烷、环磷酰胺和X射线照射。因此，可通过根据dThdPase状态选择最合适的患者群体和/或将其与dThdPase上调剂联合使用来优化卡培他滨的疗效。卡培他滨具有5-FU所没有的其他特性，如在小鼠肿瘤模型中具有强大的抗转移和抗恶病质作用。基于这些特性，卡培他滨在癌症治疗中可能具有巨大潜力。
