Locoregional administration of 5-fluoro-2′-deoxyuridine (FdUrd) in Novikoff hepatoma in the rat: effects of dose and infusion time on tumor growth and on FdUrd metabolite levels in tumor tissue as determined by19F-NMR spectroscopy

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Abstract
The influence of infusion time and dose on the anticancer efficacy of 5-fluoro-2′-deoxyuridine (FdUrd) was investigated using a locoregional therapy model: Novikoff hepatoma transplanted i.m. into the thigh of Wistar rats and FdUrd infusion via a catheter implanted in the femoral artery. In experiment A the FdUrd dose (five daily doses of 12, 19 and 30 mg/kg) and the duration of administration (bolus, 1 h, 5 h, and 24 h) were varied. The change in tumor volume following treatment and the number of rats showing regression vs progression served as indicators of therapy response. The results showed a clear dose dependence, and for each infusion time the 30 mg/kg dose was the most effective, without any signs of general toxicity. At this dose the longest infusion time (24 h) was less effective (regression in three of six rats) compared with 1-h or 5-h treatments (four of five in regression). In experiment B either one or five daily FdUrd doses (15, 30, 60 mg/kg) were administered i.a. for the same infusion times used in experiment A. After treatment, tumors were explanted ex vivo and approximately 1-g tissues samples were immediately frozen in liquid nitrogen for storage.19F-NMR spectroscopy at 11.7 T was used to quantify FdUrd metabolites [5-fluorouracil (FUra),α-fluoro-β-alanine (FβAla.), 5-fluorouracil nucleosides and nucleotides (F-Nuc)] in the solid tumor tissue samples (maintained at 4° C) with a detection threshold of about 5 nmol/g. The metabolite signal pattern indicated that FdUrd is first converted to FUra, followed by anabolism primarily to nucleotides in the oxy form (e.g. FUTP). The total amount of fluorine detected in tumor tissue increased with dose and decreased with infusion time. For all treatments FNuc could be detected, even after 24 h infusion, and their levels showed a good linear correlation with the total F. The major catabolite FβAla was present in tumor at low levels that correlated poorly with total F, indicating recirculation from other organs (e.g. liver) as the main source. Thus, the NMR method can provide detailed information regarding the efficiency of locoregional treatment (catheter function, drug uptake and metabolism). Initial results of non-invasive in vivo NMR experiments are also presented.