The tegafur-based dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines, UFT/leucovorin (ORZEL) and S-1: a review of their clinical development and therapeutic potential.
Protracted intravenous regimens of fluorouracil (5-FU) may be superior and better tolerated than intravenous bolus dosing. An effective oral regimen would allow a protracted course of 5-FU without the need for central venous lines and the associated increase in complications. Approximately 85% of 5-FU is degraded by dihydropyrimidine dehydrogenase (DPD); inhibition of this enzyme pathway can increase the amount of circulating 5-FU. Two oral fluoropyrimidines commonly referred to as DPD inhibitory fluoropyrimidines, or DIFs, UFT plus leucovorin (LV) and S-1 are reviewed herein. These agents represent an approach to more convenient, less toxic 5-FU therapy. In two multicenter, randomized, phase III trials in patients with advanced colorectal cancer, UFT/LV produced equivalent activity compared with intravenous 5-FU/LV but with significantly less major toxicity. The predominant side effect of UFT, diarrhea, is generally self-limited and easily managed. Myelosuppression and hand-foot syndrome were rarely noted in the schedules used in these trials. S-1 has demonstrated promising activity in phase II trials conducted in patients with gastric, colorectal, breast, and head and neck cancers. Ongoing trials are defining the roles of these agents in a variety of malignancies.
Hoff
P M
PM
Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D042943:Dihydrouracil Dehydrogenase (NADP); D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010094:Oxonic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use; D005641:Tegafur / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014498:Uracil / Q000008:administration & dosage / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; C079198:S 1 (combination); D005641:Tegafur; D014498:Uracil; D010094:Oxonic Acid; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin