AIMS: Oral administration of 5-fluorouracil (FUra), an important cytotoxic agent, is limited by a wide variation in bioavailability. 5'-deoxy-5-fluorouridine (dFUrd), a masked form of FUra, has shown promise clinically when given intravenously or orally as a solution or tablet. This study investigates the efficacy of an oral capsule formulation of dFUrd in generating continuous systemic levels of this compound in cancer patients. METHODS: Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1-5, at intervals of 4 weeks. The doses of dFUrd were 600 mg m-2 three times daily, 800 mg m-2 three times daily, and 1000 mg m-2 three times daily, on cycles one, two and three, respectively (total dose 36 g m-2 ). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6-dihydro-5-fluorouracil (FUraH2 ), were monitored in six patients at each dose level. RESULTS: All six patients completed the study, receiving three different doses over a 3 month period, following which one had achieved a partial response, one had stable disease, and four had developed progressive disease. Side-effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decreased with increasing dose; 2.7, 2.0 and 1.3 l min-1 m-2, following doses of 600, 800 and 1000 mg m-2, respectively. The mean elimination half-life of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUrd was rapidly absorbed with a lag time of less than 20 min. The mean elimination half-life (t1/2, z ) of oral dFUrd was 32-45 min in the dose range 600-1000 mg m-2. The AUC of FUra and FUraH2 increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailability of oral dFUrd was 34-47%. CONCLUSIONS: dFUrd, which selectively releases the antimetabolite FUra in tumour cells, can be given orally at doses of 600-1000 mg m-2 three times daily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.
AIMS: Oral administration of 5-fluorouracil (FUra), an important cytotoxic agent, is limited by a wide variation in bioavailability. 5'-deoxy-5-fluorouridine (dFUrd), a masked form of FUra, has shown promise clinically when given intravenously or orally as a solution or tablet. This study investigates the efficacy of an oral capsule formulation of dFUrd in generating continuous systemic levels of this compound in cancerpatients. METHODS: Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1-5, at intervals of 4 weeks. The doses of dFUrd were 600 mg m-2 three times daily, 800 mg m-2 three times daily, and 1000 mg m-2 three times daily, on cycles one, two and three, respectively (total dose 36 g m-2 ). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6-dihydro-5-fluorouracil (FUraH2 ), were monitored in six patients at each dose level. RESULTS: All six patients completed the study, receiving three different doses over a 3 month period, following which one had achieved a partial response, one had stable disease, and four had developed progressive disease. Side-effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decreased with increasing dose; 2.7, 2.0 and 1.3 l min-1 m-2, following doses of 600, 800 and 1000 mg m-2, respectively. The mean elimination half-life of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUrd was rapidly absorbed with a lag time of less than 20 min. The mean elimination half-life (t1/2, z ) of oral dFUrd was 32-45 min in the dose range 600-1000 mg m-2. The AUC of FUra and FUraH2 increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailability of oral dFUrd was 34-47%. CONCLUSIONS:dFUrd, which selectively releases the antimetabolite FUra in tumour cells, can be given orally at doses of 600-1000 mg m-2 three times daily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.
Authors: E A de Bruijn; L Remeyer; U R Tjaden; C Erkelens; L M de Brauw; C J van de Velde Journal: Biochem Pharmacol Date: 1986-08-01 Impact factor: 5.858
Authors: P B Vermeulen; D Verhoeven; G Hubens; E Van Marck; G Goovaerts; M Huyghe; E A De Bruijn; A T Van Oosterom; L Y Dirix Journal: Ann Oncol Date: 1995-01 Impact factor: 32.976
Authors: S van der Heyden; E Gheuens; W van de Vrie; D Van Bockstaele; A Van Oosterom; A Eggermont; E A De Bruijn Journal: Jpn J Cancer Res Date: 1994-01