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A non-radioactive method to determine 5-Fluorouracil(5FU) incorporation into DNA has been developed. Isolated DNA was enzymatically degraded to bases and the resulting 5FU was measured with standard gas-chromatography coupled to mass spectrometry(GC-MS) and compared with that of radioactive 5FU in a cell line. Incorporation into DNA of the murine Colon 26-B tumor treated with maximal tolerated doses of 5FU and fluorodeoxyuridine(FUdR) was maximal after 2 hour and was 15.4 and 71.0 fmol/µg DNA, respectively. After a plateau for about 3 days a decrease was observed to ± 2 fmol/µg DNA after 10 days. The assay is very sensitive and reproducible and can be used in a clinical setting. [ABSTRACT FROM AUTHOR]

CSF N-acetylaspartylglutamate (NAAG) has been found to be elevated in some hypomyelinating disorders. This study addressed the question whether it could be used as a marker for hypomyelination and as a means to distinguish between hypomyelinating disorders biochemically. We have measured CSF NAAG in a cohort of 28 patients with hypomyelination with known and unknown aetiology. NMG was found to be elevated in 7 patients, but was normal in the majority, including patients with defined hypomyelinating disorders. CSF NAAG is not a universal marker of hypomyelination, and the mechanism of its elevation remains poorly understood. [ABSTRACT FROM AUTHOR]

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/m2. The plasma Cmax values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1–2 h were in the ranges 5.8–13 μM, 0.4–2.4 μM, 0.026–1.337 μM, and 1.1–3.6 μM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03–0.25 μM to 3.6–9.4 μM after 2–4 h, and 0.09–0.9 μM 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 μmol·min/l, respectively. The t1/2 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-β-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 μM and uracil was in the micromolar range (up to 7 μM), 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. [ABSTRACT FROM AUTHOR]