Dihydropyrimidine dehydrogenase inhibition as a strategy for the oral administration of 5-fluorouracil: utility in the treatment of advanced colorectal cancer.
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.
Schmoll
Hans-Joachim
HJ
Department of Internal Medicine, Martin Luther University Halle, Halle/Saale, Germany. hans-joachim.schmoll@medizin.uni-halle.de
D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors*; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil