Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue

Anti‐metastatic effect of capecitabine on human colon cancer xenografts in nude mouse rectum

“…1 In humans, it is sequentially converted first to 5Ј-deoxy-5-fluorocytidine by carboxylesterase located in the liver, then to 5Ј-deoxy-5-fluorouridine by cytidine deaminase also with high activity in the liver and in various solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) with high activity in many types of tumors. [1][2][3] This oral fluoropyrimidine has an advantage over parental therapy with 5-FU in its potential for affording patients greater convenience and comfort. 4 -6 Randomized clinical trials that compared capecitabine with parenteral 5-FU/leucovorin against metastatic colorectal cancer demonstrated that capecitabine provides at least equivalence, a favorable benefit-risk ratio and greater patient preference making it an acceptable replacement for 5-FU/leucovorin.…”

“…These include the introduction of 2 novel cytotoxic compounds. Another strategy that has received attention has been the development of several oral forms of fluoropyrimidine, offering an alternative route of administration to intravenous 5-FU 1 . Capecitabine (N 4 -pentyloxycarbonyl-5Ј-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is designed to be activated to 5-FU by 3 sequential steps of enzyme reactions.…”

“…Capecitabine (N 4 -pentyloxycarbonyl-5Ј-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is designed to be activated to 5-FU by 3 sequential steps of enzyme reactions. 1 In humans, it is sequentially converted first to 5Ј-deoxy-5-fluorocytidine by carboxylesterase located in the liver, then to 5Ј-deoxy-5-fluorouridine by cytidine deaminase also with high activity in the liver and in various solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) with high activity in many types of tumors. [1][2][3] This oral fluoropyrimidine has an advantage over parental therapy with 5-FU in its potential for affording patients greater convenience and comfort.…”

A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer

“…Capecitabine achieves longterm inhibition of the target enzyme thymidylate synthase, and in this way mimics the continuous intravenous infusion of 5FU. It has the additional important theoretical advantage of the targeted production of 5FU in malignant cells via the enzyme thymidine phosphorylase (TP), which is overexpressed in tumour vs normal tissue (Miwa et al, 1998). In addition, radiotherapy is known to further upregulate TP, and in xenograft models, capecitabine and radiation have shown supra-additive activity (Sawada et al, 1999).…”

Randomised, phase II trial comparing oral capecitabine (Xeloda®) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines

“…Capecitabine (Xeloda 1 ) is a tumour-selective fluoropyrimidine carbamate designed to mimic continuous infusion 5-FU and to generate 5-FU preferentially in tumour tissue by exploiting the higher concentrations of thymidine phosphorylase (TP) found in malignant cells compared with normal cells (Miwa et al, 1998). Following oral administration, capecitabine passes intact through the intestinal mucosa and is rapidly and extensively metabolised via a sequential triple enzyme pathway.…”