Comparison of 5-fluorouracil and ftorafur. I. Quantitative and qualitative differences in toxicity to mice.

5-Fluorouracil (5-FU) was compared to ftorafur, a fraudulent nucleoside analog which acts as a depot form of 5-FU, with respect to influence of dosage level and schedule of administration on toxicity in mice. When the drugs were administered daily and the duration of treatment was varied from a single dose to 32 daily treatments, the toxicity of 5-FU proved to be somewhat more than cumulative. On the other hand, the toxicity of ftorafur on daily treatment was less than cumulative. As a single treatment ftorafur was about half as toxic as 5-FU on an mg/kg basis. When the drugs were administered daily for 12 days the LD50 of ftorafur was about sevenfold that of 5-FU. When the drugs were administered as two treatments and the interval between the two treatments was varied from 0 to 14 days, it was found that 5-FU was considerably more toxic at an interval of 2-7 days than when two doses were administered simultaneously. Appreciable recovery of mice from the initial dose of 5-FU did not occur until sometime between 7 and 10 days. Host recovery from ftorafur toxicity was apparent by 2 days. The dose-mortality curves form both drugs were steep. The decreased toxicity with repeated treatment with ftorafur relative to 5-fu was not due to a decrease in the metabolism of ftorafur to 5-FU, which was much more extensive in mice compared to previously reported pharmacokinetic studies in other species. At equitoxic doses on a daily X 5 schedule, 5-FU and ftorafur had similar myelosuppressive activity. Ftorafur was, however, clearly less suppressive to both humoral and cell-mediated immunity than was 5-FU.