Ishikawa T, Utoh M, Sawada N, Nishida M, Fukase Y, Sekiguchi F, Ishitsuka H
Cytostatics Group, Nippon Roche Research Center, Kamakura-City, Kanagawa, Japan.
Biochem Pharmacol. 1998 Apr 1;55(7):1091-7. doi: 10.1016/s0006-2952(97)00682-5.
Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that is converted to 5-fluorouracil (5-FUra) by three enzymes located in the liver and tumors; the final step is the conversion of 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-FUra by thymidine phosphorylase in tumors. The present study compared the efficacy of capecitabine and 5-FUra at their maximum tolerated doses in CXF280, HCT116, COLO205, and WiDr human colon cancer xenograft models, and measured subsequent 5-FUra and 5'-dFUrd levels in tumors and in the plasma and muscle. Capecitabine was effective in the first three models, whereas 5-FUra was effective only in CXF280, which is a cell line highly susceptible to fluoropyrimidines. In the three susceptible models, 5-FUra AUCs in tumors after capecitabine administration were 210 to 303 nmol x hr/g, whereas those after 5-FUra administration were 8.54 to 13.1 nmol x hr/g. In addition, capecitabine gave higher levels of 5-FUra AUC in tumors than in plasma (114- to 209-fold higher) and muscle (21.6-fold higher), whereas 5-FUra was not selectively distributed to tumors. In the refractory model, WiDr, 5-FUra AUC in tumors after capecitabine administration was only 62.8 nmol x hr/g, although the level of the intermediate metabolite 5'-dFUrd was high (AUC: 695 nmol x hr/g). The ratio of 5-FUra/5'-dFUrd levels in the WiDr tumors was 0.09, which was 23.8-fold lower than that in the HCT116 tumors. The mechanism of resistance would be the inefficient conversion of 5'-dFUrd to 5-FUra by thymidine phosphorylase in tumors. Thus, capecitabine might show its high efficacy as a result of delivering high levels of 5-FUra selectively to the tumors.
卡培他滨（N4-戊氧羰基-5'-脱氧-5-氟胞苷）是一种新型氟嘧啶氨基甲酸酯，通过肝脏和肿瘤中的三种酶转化为5-氟尿嘧啶（5-FUra）；最后一步是肿瘤中的胸苷磷酸化酶将5'-脱氧-5-氟尿苷（5'-dFUrd）转化为5-FUra。本研究比较了卡培他滨和5-FUra在CXF280、HCT116、COLO205和WiDr人结肠癌异种移植模型中最大耐受剂量下的疗效，并测量了随后肿瘤、血浆和肌肉中的5-FUra和5'-dFUrd水平。卡培他滨在前三种模型中有效，而5-FUra仅在对氟嘧啶高度敏感的细胞系CXF280中有效。在三种敏感模型中，卡培他滨给药后肿瘤中的5-FUra曲线下面积（AUC）为210至303nmol·hr/g，而5-FUra给药后的AUC为8.54至13.1nmol·hr/g。此外，卡培他滨使肿瘤中的5-FUra AUC水平高于血浆（高114至209倍）和肌肉（高21.6倍），而5-FUra没有选择性地分布到肿瘤中。在难治性模型WiDr中，卡培他滨给药后肿瘤中的5-FUra AUC仅为62.8nmol·hr/g，尽管中间代谢产物5'-dFUrd的水平很高（AUC：695nmol·hr/g）。WiDr肿瘤中5-FUra/5'-dFUrd水平的比值为0.09，比HCT116肿瘤中的比值低23.8倍。耐药机制可能是肿瘤中的胸苷磷酸化酶将5'-dFUrd低效转化为5-FUra。因此，卡培他滨可能由于将高水平的5-FUra选择性地输送到肿瘤中而显示出其高效性。
