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| Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients |
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| Author(s): Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B |
| Source: CANCER CHEMOTHERAPY AND PHARMACOLOGY Volume: 45 Issue: 4 Pages: 291-297 Published: APR 2000 |
| Times Cited: 294 References: 22 |
| Abstract: Purpose: Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. Methods: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m(2) of capecitabine twice daily p.o. for 5-7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. Results: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. Conclusions: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues. |
| Document Type: Article |
| Language: English |
| Reprint Address: Reigner, B (reprint author), F Hoffmann La Roche & Co Ltd, Dept Clin Pharmacol, Grenzacherstr 124, CH-4070 Basel, Switzerland |
Addresses:
1. F Hoffmann La Roche & Co Ltd, Dept Clin Pharmacol, CH-4070 Basel, Switzerland
2. Hosp Rudolfstiftung, Dept Oncol, Vienna, Austria
3. Univ Aberdeen, Dept Med & Therapeut, Aberdeen, Scotland
4. Roche Prod Ltd, Dept Clin Pharmacol, Welwyn Garden City AL7 3AY, Herts England
5. F Hoffmann La Roche & Co Ltd, Dept Biostat, CH-4002 Basel, Switzerland
6. Nippon Roche Res Ctr, Kamakura, Kanagawa 247 Japan |
| Publisher: SPRINGER VERLAG, 175 FIFTH AVE, NEW YORK, NY 10010 USA |
| Subject Category: Oncology; Pharmacology & Pharmacy |
| IDS Number: 298VE |
| ISSN: 0344-5704 |
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