Improving 5-FU with a novel dihydropyrimidine dehydrogenase inactivator.
GW776C85 is a new drug that has been shown to be an effective inactivator of dihydropyrimidine dehydrogenase (DPD). Preclinical studies demonstrated that administration of GW776C85 with 5-fluorouracil (5-FU) resulted in several desirable pharmacologic effects. Initial clinical data on 5-FU combined with GW776C85 suggest potentially increased antitumor activity in at least some malignancies with tolerable toxicity, as well as several distinct economic and quality-of-life advantages including the following: (1) The possibility of administering 5-FU as an oral drug due to excellent bioavailability of 5-FU following inactivation of DPD; (2) a cost-effective alternative to continuous or protracted infusion of 5-FU without the need for hospitalization or surgical placement of an intravenous access and availability of an ambulatory pump; and (3) potential for less interpatient variation of 5-FU toxicity (e.g., in host tissues, such as bone marrow and gastrointestinal mucosa cells) due to inactivation of DPD in essentially all patients treated, permitting better 5-FU dosing guidelines. Finally, because tumors may theoretically become resistant to 5-FU by increased levels of DPD, the use of GW776C85 to inactivate DPD may provide a potential means by which tumor resistance can be reversed.
Diasio
R B
RB
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA.
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D042943:Dihydrouracil Dehydrogenase (NADP); D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000191:economics / Q000494:pharmacology*; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000031:analogs & derivatives* / Q000191:economics / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil