5-ETHYNYLURACIL (776C85) - MODULATION OF 5-FLUOROURACIL EFFICACY AND THERAPEUTIC INDEX IN RATS BEARING ADVANCED COLORECTAL-CARCINOMA

5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimid ine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FU ra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcin oma. Two schedules were studied: (a) FUra daily for 4 days i.v. push ( daily x 4); and (6) FUra administered i.v. push weekly for 3 weeks (we ekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 m g/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra a lone and for FUra in combination with EU. Although EU was not toxic an d not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was sche dule dependent, yielding 13% complete and sustained tumor regression o n the weekly schedule and no complete and sustained tumor regression o n the daily schedule. The combination of FUra and EU produced 100% com plete and sustained tumor regression on both schedules. The therapeuti c index was less than or equal to 1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(p hosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(ph osphonacetyl)-L-aspartate induced minimum improvements on the daily sc hedule and only increased the therapeutic index to 1.5 on the weekly s chedule. Because a 4-day continuous infusion of FUra alone at the maxi mum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.