Capecitabine: preclinical pharmacology studies
Capecitabine: preclinical pharmacology studies
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DOI：
10.1023/a:1006497231579
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发表时间：
2000-11-01
影响因子：
3.4
通讯作者：
Ishitsuka, H
中科院分区：
文献类型：
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作者：
Ishitsuka, H
卡培他滨（Capecitabine，N-4-pentyloxy carbonyl-5 '-deoxy-5-fluorocytidine）是一种新型的氟嘧啶氨基甲酸酯，其被设计为通过位于肝脏和肿瘤中的三种酶顺序地转化为5-氟尿嘧啶（5-FU）;最后一步是通过肿瘤中的胸苷磷酸化酶（dThdR）将5'-脱氧-5-氟尿嘧啶（5 '-DFUR）转化为5-FU。在人类癌症异种移植模型中，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）。肿瘤5-FU水平也远高于静脉注射等毒性剂量的5-FU所达到的水平。卡培他滨及其中间体本身无细胞毒性，但在转化为5-FU后有效。5-FU的这种肿瘤选择性递送确保了比其他氟嘧啶更大的疗效和更有利的安全性特征。在研究的24种人类癌症异种移植模型中，卡培他滨在更宽的剂量范围内更有效，并且具有比5-FU、UFT或其中间代谢产物5 '-DFUR更广谱的抗肿瘤活性。异种移植物对卡培他滨的敏感性与肿瘤dTh水平相关。此外，在卡培他滨难治的异种移植模型中，肿瘤中dThdR将5 '-DFUR转化为5-FU是不足的。此外，卡培他滨的疗效通过dThd 4上调剂如紫杉烷类和环磷酰胺增强。因此，卡培他滨的疗效可以通过基于dThdR状态选择最合适的患者群体和/或通过将其与dThdR上调剂组合来优化。卡培他滨具有5-FU未发现的其他特性，例如在小鼠肿瘤模型中的强效抗转移和抗惊厥作用。卡培他滨可能在癌症治疗中具有巨大的潜力。
Capecitabine (N-4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors; the final step is the conversion of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU by thymidine phosphorylase (dThdPase) in tumors. In human cancer xenograft models, 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 intravenous administration of 5-FU at equitoxic doses. Capecitabine and its intermediates are not cytotoxic by themselves, but become effective after their conversion to 5-FU. This tumor selective delivery of 5-FU ensured greater efficacy and a more favorable 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 taxanes and cyclophosphamide. 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 this profile, capecitabine may have substantial potential in cancer treatment.