5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice

Purpose: PN401, an oral prodrug of uridine yields more bioavailable uridine than oral administration of uridine itself. PN401 may therefore be useful for permitting dose escalation of 5-fluorouracil (5-FU) with consequent improvements in antitumor efficacy. Experimental design: Female BALB/c mice (Colon 26 adenocarcinoma) were treated with 5-FU with PN401 to define the MTD, and pharmacokinetic analyses were done. A comparison of 5-FU/PN401 was made to 5-FU/eniluracil (EU) and 5-FU/LV. The best timing of the first dose of PN401 relative to 5-FU was evaluated by administering groups of mice PN401 beginning 2, 24, or 48 h after 5-FU dose. Results: The MTD of 5-FU was 100 mg/kg/week whereas the MTD of 5-FU + PN401 was 200 mg/kg/week. A complete response (CR) of 80% and partial response (PR) of 20% was observed with 5-FU (200 mg/kg) + PN401, CR of 40% and PR of 60% with 5-FU (175 mg/kg) + PN401, PR of 10% with 5-FU (150 mg/kg) + PN401 while no response with 5-FU (100 mg/kg) + PN401. Analysis of 5-FU pharmacokinetics displayed nonlinearity as a function of administered dose in mice. In the comparison study, the best response was achieved with PN401 when compared to EU and LV. Mice that did not receive PN401 died by day 12, while other groups were alive at day 31. The proportion of mice surviving was highest in the group which received PN401 at 2 h followed by 24 and 48 h. Conclusions: There is a threshold 5-FU dose after which the efficacy is dramatically improved—in mice bearing Colon 26 adenocarcinoma, that threshold is a dose of >150 mg/kg/week, and the increased efficacy correlates with about a fourfold increase in the AUC of 5-FU. PN401 used to rescue mice from the lethal toxicity of 5-FU entails that PN401 can be used as an antidote even when used up to 48 h after a 5-FU overdose.