Dihydropyrimidine dehydrogenase inhibition as a strategy for the oral administration of 5-fluorouracil: utility in the treatment of advanced colorectal cancer
作者:
Hans-Joachim Schmoll,
期刊:
Anti-Cancer Drugs
(OVID Available online 2003)
卷期:
Volume 14,
issue 9
页码: 695-702
ISSN:0959-4973
年代: 2003
出版商: OVID
关键词: colorectal cancer;DIF;dihydropyrimidine dehydrogenase;eniluracil;oral fluoropyrimidine;S-1;tegafur
数据来源: OVID
摘要:
Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) catabolism, has been a key target for the development of novel oral fluoropyrimidines. DPD-inhibiting oral fluoropyrimidines showing promise in early clinical studies included UFT (the 5-FU prodrug, tegafur, plus the DPD substrate, uracil), eniluracil (an irreversible DPD inhibitor that improves the oral bioavailability of 5-FU) and S-1 (tegafur plus a reversible DPD inhibitor, 5-chloro-2,4-dihydroxypyridine, and oxonic acid). However, results from phase II/III trials evaluating these agents as first-line therapy for metastatic colorectal cancer have been disappointing. Although DPD-inhibiting oral fluoropyrimidines have some activity in colorectal cancer and oral administration provides significant convenience advantages, the inferior efficacy of UFT/leucovorin and eniluracil/5-FU versus 5-FU/leucovorin in phase III trials does not support the use of these compounds. A feasible regimen for the phase III development of S-1 outside Japan has not been defined. Thus the DPD-inhibiting oral fluoropyrimidines have failed to fulfill their early promise: clinical data indicate that none of these compounds is likely to improve outcomes for patients with metastatic colorectal cancer.
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