Original PaperDesign of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue
Introduction
Many strategies for selectively delivering anticancer drugs to tumours have been reported. Specifically, prodrug activation by enzymes located in tumour tissues has been discussed. We have previously shown that 5′-deoxy-5-fluorouridine (5′-dFUrd) is not itself cytotoxic but becomes effective only after conversion to the active drug 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase), which is preferentially located in tumour tissues[1]. Since 5′-dFUrd produces higher levels of 5-FU in tumours than in normal counterparts[2], it has been found to be more effective than 5-FU and other fluoropyrimidines in various studies with mouse transplantable tumour models, particularly in terms of therapeutic indices1, 3, 4. 5′-dFUrd is being marketed in Japan, China and Korea (Furtulon®) for the treatment of breast, colorectal, gastric and other cancers, while it is being clinically assessed in the EU.
The major drawback of cancer treatment with 5′-dFUrd, given orally, is its dose-limiting side-effect, diarrhoea[5]. When 5′-dFUrd passes through the intestinal mucosal membrane, 5′-dFUrd is thought to cause the intestinal toxicity of 5-FU generated in the intestine[6]. PyNPase exists predominantly as thymidine phosphorylase (dThdPase) in humans[7], while it is predominantly as uridine phosphorylase in rodents[8]. We, therefore, tried to identify a new fluoropyrimidine which could pass through the intestinal tract, by applying an approach of prodrug activation by additional enzymes. These studies created a novel fluoropyrimidine carbamate, capecitabine, which is sequentially converted to 5′-dFUrd by carboxylesterase and cytidine (Cyd) deaminase with unique tissue localisation in humans and then to 5-FU by dThdPase. In this report, we describe the tissue distribution of these enzymes for capecitabine activation. In addition, we describe that capecitabine and its intermediate metabolites were not themselves cytotoxic but became effective once they were converted to the active drug 5-FU.
Section snippets
Animals and tissues
Male and female BALB/c nu/nu mice were obtained from CLEA Japan Co., Ltd, (Tokyo, Japan). Male BDF1 mice were obtained from SLC Inc. (Hamamatsu, Japan). The mice were observed for at least 1 week and then used when 6 weeks old.
Chemicals
Capecitabine and 6-amino-5-chlorouracil (ACU, an inhibitor of dThdPase) were synthesised by methods described elsewhere9, 10. 5-FU and a combination drug of uracil and tegafur (UFT) were purchased from Kyowa Hakko K.K. and Taiho Pharma Co. (Tokyo, Japan), respectively,
References (21)
- et al.
Pyrimidine nucleosidases. Their classification and relation to uric acid ribonucleoside phosphorylase
J Biol Chem
(1965) - et al.
Protein measurement with the Folin phenol reagent
J Biol Chem
(1951) - et al.
Expression of cytidine deaminase in human solid tumors and its regulation by 1α, 25-dihydroxyvitamin D3
Biochim Biophys Acta
(1996) - et al.
Role of uridine phosphorylase for antitumor activity of 5′-deoxy-5-fluorouridine
Gann
(1980) - et al.
Tissue distribution of 5′-deoxy-5-fluorouridine and derived 5-fluorouracil in tumor-bearing mice and rats
Gann
(1980) - et al.
Comparative studies on the antitumor activity of fluorinated pyrimidines, 5′-DFUR, Tegafur, UFT and FUra, with various murine tumors
Jpn J Cancer Chemother
(1988) - Uehara N, Baba H, Nitta K, et al. The therapeutic effect of orally administered 5′-deoxy-5-fluorouridine,...
- et al.
A comparative study between 5′-DFUR and Tegafur in recurrent breast cancer
Jpn J Cancer Chemother
(1985) - Ninomiya Y, Miwa M, Eda H, et al. Comparative antitumor activity and intestinal toxicity of 5′-deoxy-5-fluorouridine...
- et al.
Specificity of pyrimidine nucleoside phosphorylases and the phosphorolysis of 5-fluoro-2′-deoxycytidine
Cancer Res
(1980)