Effect of thymidine on the toxicity and antitumor activity of ftorafur

The effects of thymidine (TdR) on the toxicity and antitumor activity of ftorafur (FT), a 5-FU analog, were determined. The LD10 of FT was 130, 430, and 680 mg/kg, respectively, when FT was administered ip in the following treatment schedules: (a) daily for 9 days, (b) every 4th day for three treatments, and (c) 1 day only. When FT was administered simultaneously with 250 mg/kg of TdR, the LD10 was 13, 62, and 630 mg/kg in the respective treatment schedules. Lethargy was observed in mice when the daily dose of FT was greater than or equal to 150 mg/kg. FT alone was active (% treated/control [T/C] = 153) against ascites P388 murine leukemia only at high, single doses. Simultaneous administration of FT and 250 mg/kg of TdR at or below the LD10 dose of FT resulted in an increase in the antitumor activity to a % T/C of 217 (daily, Days 1-9) and 188 (daily, Days 1, 5, and 9). The activity of FT administered simultaneously with TdR on Day 1 only (%T/C = 142) was lower than that for FT alone. Using a treatment schedule of Days 1, 5, and 9, a TdR/FT mol ratio of greater than or equal to 2.0 seems necessary to achieve an increase in therapeutic value against P388 murine leukemia. This may explain the lack of increase in activity against P388 when 250 mg/kg of TdR was coadministered with FT on Day 1 only. FT alone or coadministered with 250 mg/kg of TdR was equally active against L1210 ascites tumor at doses up to the LD10 with daily treatments on Days 1, 5, and 9 and on Days 1-9; the doses of FT, however, were below those which cause lethargy.