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| Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts |
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| Author(s): Ishikawa T, Utoh M, Sawada N, Nishida M, Fukase Y, Sekiguchi F, Ishitsuka H |
| Source: BIOCHEMICAL PHARMACOLOGY Volume: 55 Issue: 7 Pages: 1091-1097 Published: APR 1 1998 |
| Times Cited: 126 References: 11 |
| Abstract: 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-EUra 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 turners. 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 (AUG: 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-EUra by thymidine phosphorylase in tumors. Thus, capecitabine might show its high efficacy as a result of delivering high levels of 5-EUra selectively to the tumors. (C) 1998 Elsevier Science Inc. |
| Document Type: Article |
| Language: English |
| Reprint Address: Ishitsuka, H (reprint author), Nippon Roche Res Ctr, Cytostat Grp, Kajiwara 200, Kanagawa 247, Japan |
Addresses:
1. Nippon Roche Res Ctr, Cytostat Grp, Kanagawa 247, Japan |
| Publisher: PERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND |
| Subject Category: Pharmacology & Pharmacy |
| IDS Number: ZG375 |
| ISSN: 0006-2952 |
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