Potentiation of 5-fluorouracil efficacy by the dihydrouracil dehydrogenase inhibitor, 5-benzyloxybenzyluracil.
5-Benzyloxybenzyluracil (BBU) is the most potent inhibitor (Ki approximately 30 nM) of dihydrouracil dehydrogenase (EC 1.3.1.2), the first enzyme in the catabolic pathway of pyrimidine bases and their analogues, including 5-fluorouracil (FUra). The effect of BBU on modulating the chemotherapeutic efficacy and host toxicity of FUra was evaluated using human colon carcinoma DLD-1 grown in culture and as xenografts in anti-thymocyte serum (ATS)-immunosuppressed mice. The effect of BBU on FUra-induced host toxicity was also studied in nontumor-bearing-ATS-immunosuppressed and immunocompetent mice. At 0.2 microM, BBU potentiated growth inhibition by FUra of DLD-1 cells in culture (the concentration that produces 50% inhibition of cell growth was 0.48 microM at 3 h) by 1.3-fold (from 45 to 28% growth). BBU also enhanced the cytocidal effect of FUra (0.48 microM, 3 h) against DLD-1 grown in soft agar by 3-fold (from 45 to 15% growth). In ATS-immunosuppressed mice bearing DLD-1 xenografts, coadministration of BBU with FUra enhanced not only the efficacy of FUra in killing the tumor but also protected the host from FUra-induced host toxicity. This was 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 increased host survival from 83 to 100%. The enhancement of tumor kill and protection from host toxicity induced by FUra was also evident at higher 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%. Host protection from FUra-induced toxicity was corroborated further by the protective effect of BBU, inferred from the increase in the dose that produces 50% mortality in ATS-immunosuppressed (from 135 to 195 mg/kg/day x 2) and immunocompetent (from 250 to 300 mg/kg/day x 2) mice. Therefore, coadministration of BBU improved the therapeutic index of FUra by 5.5-fold (from 2.3 to 12.6) as a result of potentiating the antitumor efficacy of FUra and reducing its induced host toxicity. This protection by BBU sharply contrasts with the effect of most other dihydrouracil dehydrogenase inhibitors, which at therapeutic doses increase host toxicity by FUra. These findings may lead to a more successful use of FUra in cancer chemotherapy.
Naguib
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Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912.
Hao
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el Kouni
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D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D050744:Dihydrouracil Dehydrogenase (NAD+); D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007108:Immune Tolerance; D007928:Lethal Dose 50; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
C068991:5-benzyloxybenzyluracil; D014498:Uracil; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D005472:Fluorouracil