Oral eniluracil/5-FU for advanced colon and breast carcinomas.
5-fluorouracil (5-FU) is irreversibly catabolized to dihydrofluorouracil, an inactive metabolite, by the enzyme dihydropyrimidine dehydrogenase (DPD). This catabolic pathway is a critical step in determining 5-FU availability for conversion to nucleotides and eventual incorporation into either RNA or DNA. Inactivation of DPD, therefore, is an approach to enhance the availability of 5-FU for potential improved therapeutic effect. Preclinical animal and human studies have demonstrated that eniluracil is an effective inactivator of DPD. Phase I studies have been completed showing the tolerability of two dosing schedules, including (1) a chronic schedule with twice-daily administration of eniluracil plus oral fluorouracil (5-FU) (10:1 ratio) for 28 days, and (2) a schedule of eniluracil administered daily on days 1-7 with oral 5-FU once daily on days 2-6. The phase I trials have demonstrated limited toxicities including diarrhea, mucositis, and neutropenia. Follow-up clinical trials have targeted colon and breast cancers in particular.
Benson
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AB
Division of Hematology/Oncology, Department of Medicine, Clinical Investigations Program, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. a-benson@northwestern.edu
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D042943:Dihydrouracil Dehydrogenase (NADP); D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005544:Forecasting; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D014498:Uracil / Q000008:administration & dosage* / Q000031:analogs & derivatives*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil