Initial clinical experience with oral ftorafur and oral 6R,S leucovorin in advanced colorectal carcinoma

Manzuik, L.V.; Переводчикова, Н И; Горбунова, В. А.; Singin, A. S.; Gerasimova, G.S.; Бычков, М Б; Rustum, Youcef M.; Creaven, Patrick J.

doi:10.1016/0959-8049(93)90129-4

Cited by 7 publications

(1 citation statement)

References 5 publications

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“…For this reason, the T F dose was slightly lower than that used in monotherapy (1 g/m2/day), but always within the accumulative recommended dose of 30 g [4], A recent cooperative study by Manzuik et al [10] of oral T F at different dose levels (650-1,250 mg/m2/day x 21 days) together with oral LV 495 mg/day (divided into 5 doses) recommends a T F dose of approximately 900 mg/m2, in spite of the fact that the toxicity recorded at this dose level is considerable (30 episodes of grade III toxicity in 27 completed treatment courses).…”

Section: Discussionmentioning

confidence: 99%

Clinical Experience with Tegafur and Low Dose Oral Leucovorin: A Dose-Finding Study

Nogué

Saigí²,

Seguí³

1995

Oncology

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Tegafur is an effective oral fluoropyrimidine that shows the same activity as 5-fluorouracil for a similar spectrum of cancers. Their biochemical modulation with oral Leucovorin (LV) attempts to simulate treatment with a continuous infusion of 5-fluorouracil and LV with the added advantage of outpatient administration. Thirty-three patients with advanced adenocarcinoma were included in the study. The treatment consisted of tegafur, 0.75 g/m²/day, for 21 days, with oral LV at different dose levels, 15, 30, 45, 60 and 90 mg/day, in a 28-day cycle. A correlation between the LV dose and an increase in grade III/IV toxicity (especially diarrhea, oral mucositis and fatigue) was established in the nonlinear regression model, reaching a plateau at 60 mg of LV. For the tegafur dose used, the recommended dose of LV is in the range of 45-60 mg/ day. This schedule could be considered to evaluate the possible therapeutic effect in phase II trials.

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Section: Discussionmentioning

confidence: 99%

Clinical Experience with Tegafur and Low Dose Oral Leucovorin: A Dose-Finding Study

Nogué

Saigí²,

Seguí³

1995

Oncology

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Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors

Peters

Noordhuis

Kuilenburg

et al. 2003

Cancer Chemother Pharmacol

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S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m(2). The plasma C(max) values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1-2 h were in the ranges 5.8-13 microM, 0.4-2.4 microM, 0.026-1.337 microM, and 1.1-3.6 microM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03-0.25 microM to 3.6-9.4 microM after 2-4 h, and 0.09-0.9 microM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418-1735 and 2281-8627 micromol x min/l, respectively. The t(1/2) values were in the ranges 213-692 and 216-354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2-11.9%; the urinary excretion of both fluoro-beta-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 microM and uracil was in the micromolar range (up to 7 microM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition.

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Advanced drug delivery reviews: enzyme prodrug therapy

Sherwood

1996

Advanced Drug Delivery Reviews

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Initial clinical experience with oral ftorafur and oral 6R,S leucovorin in advanced colorectal carcinoma

Cited by 7 publications

References 5 publications

Clinical Experience with Tegafur and Low Dose Oral Leucovorin: A Dose-Finding Study

Clinical Experience with Tegafur and Low Dose Oral Leucovorin: A Dose-Finding Study

Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors

Advanced drug delivery reviews: enzyme prodrug therapy

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