Modulation of 5-fluorouracil host toxicity by 5-(benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2 ',3 ',5 '-tri-O-acetyluridine, a prodrug of uridine

Administration of 200 mg/kg of 5-fluorouracil (FUra) to mice bearing human colon carcinoma DLD-1 xenografts resulted in 100% mortality. Oral administr ation of 2000 mg/kg of 2',3',5'-tri-O-acetyluridine (TAU), a prodrug of uri dine, in combination with 120 mg/kg of 5-(benzyloxybenzyl)barbituric acid a cyclonucleoside (BBBA), the most potent known inhibitor of uridine phosphor ylase (UrdPase, EC 2.4.2.3), 2 hr after the administration of the same dose of FUra completely protected the mice (100% survival) from the toxicity of FUra. This combination also reduced tumor weight by 67% compared with 46% achieved by the maximum tolerated dose (50 mg/kg) of FUra alone. Similarly, administration of BBBA plus TAU 1 hr before or 4 hr after the administrati on of FUra reduced the tumor weight by 53 and 37%, respectively. However, t hese schedules were less effective in protecting the host from the toxicity of FUra than when the treatment was carried out at 2 hr after FUra adminis tration. TAU alone did not protect from FUra host toxicity. The efficiency of the BBBA plus TAU combination in rescuing from FUra host toxicities is a ttributed to the exceptional effectiveness of this combination in raising a nd maintaining higher plasma uridine concentrations than those achieved by TAU alone or by equimolar doses of uridine (Ashour et al., Biochem Pharmaco l 51: 1601-1612, 1996). The present results suggest chat the BBBA plus TAU combination can provide a better substitute for the massive doses of uridin e required to achieve the high levels of uridine necessary to rescue or pro tect from FUra host toxicities without the toxic side-effects associated wi th such doses of uridine. The combination of TAU plus BBBA may also allow t he escalation of FUra doses for better chemotherapeutic efficacy. Alternati vely, the combination may be used as a rescue regimen in the occasional cas es where cancer patients receive a lethal overdose of FUra. BIOCHEM PHARMAC OL 60;3:427-431, 2000. (C) 2000 Elsevier Science Inc.