POTENTIATION OF 5-FLUOROURACIL EFFICACY BY THE DIHYDROURACIL DEHYDROGENASE INHIBITOR, 5-BENZYLOXYBENZYLURACIL

5-Benzyloxybenzyluracil (BBU) is the most potent inhibitor (K-i simila r to 30 nM) of dihydrouracil dehydrogenase (EC 1.3.1.2), the first enz yme in the catabolic pathway of pyrimidine bases and their analogues, including 5-fluorouracil (FUra). The effect of BBU on modulating the c hemotherapeutic efficacy and host toxicity of FUra was evaluated using human colon carcinoma DLD-1 grown in culture and as xenografts in ant i-thymocyte serum (ATS)-immunosuppressed mice. The effect of BBU on FU ra-induced host toxicity nas also studied in nontumor-bearing-ATS-immu nosuppressed and immunocompetent mice. At 0.2 mu M, BBU potentiated gr owth inhibition by FUra of DLD-1 cells in culture (the concentration t hat produces 50% inhibition of cell growth was 0.48 mu M at 3 h) by 1. 3-fold (from 45 to 28% growth). BBU also enhanced the cytocidal effect of FUra (0.48 mu M, 3 h) against DLD-1 grown in soft agar by 3-fold ( from 45 to 15% growth). In ATS-immunosuppressed mice bearing DLD-1 xen ografts, coadministration of BBU with FUra enhanced not only the effic acy of FUra in killing the tumor but also protected the host from FUra -induced host toxicity. This mas particularly evident at low doses of FUra. Coadministration of BBU (10 mg/kg/day x 2) with FUra at 30 mg/kg /day x 2 reduced tumor weight by 16-fold (from 799 to 49 mg) and incre ased host survival from 83 to 100%. The enhancement of tumor kill and protection from host toxicity induced by FUra was also evident at high er doses of FUra, albeit to a lesser degree. At 120 mg/kg/day x 2 FUra , coadministration of BBU (10 mg/kg/day x 2) reduced tumor weight from 44 to 10 mg and increased survival of the animals from 33 to 50%. Hos t protection from FUra-induced toxicity nas corroborated further by th e protective effect of BBU, inferred from the increase in the dose tha t produces 50% mortality in ATS-immunosuppressed (from 135 to 195 mg/k g/day x 2) and immunocompetent (from 250 to 300 mg/kg/day x 2) mice. T herefore, coadministration of BBU improved the therapeutic index of FU ra by 5.5-fold (from 2.3 to 12.6) as a result of potentiating the anti tumor efficacy of FUra and reducing its induced host toxicity. This pr otection by BBU sharply contrasts with the effect of most other dihydr ouracil dehydrogenase inhibitors, which at therapeutic doses increase host toxicity by FUra. These findings may lead to a more successful us e of FUra in cancer chemotherapy.