Tumor Selective Delivery of 5-Fluorouracil by Capecitabine, a New Oral Fluoropyrimidine Carbamate, in Human Cancer Xenografts

• Published in: Biochemical pharmacology 1998-04, Vol.55 (7), p.1091-1097
• Main Authors: Ishikawa, Tohru, Utoh, Masahiro, Sawada, Noriaki, Nishida, Miwa, Fukase, Yu, Sekiguchi, Fumiko, Ishitsuka, Hideo
• Format: Article
• Language: English
• Subjects: 5-fluorouracil (5-FUra); 5′-deoxy-5-fluorouridine (5′-dFUrd); Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; antitumor activity; Biological and medical sciences; Capecitabine; Chemotherapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacokinetics; Deoxycytidine - pharmacology; Female; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Fluorouracil - pharmacology; Half-Life; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; pharmacokinetics; Pharmacology. Drug treatments; prodrug; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00682-5

Capecitabine ( N 4-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 · hr/g, whereas those after 5-FUra administration were 8.54 to 13.1 nmol · 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 · hr/g, although the level of the intermediate metabolite 5′-dFUrd was high (AUC: 695 nmol · 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.