In vivo evaluation of a novel antitumor prodrug, 1-(2 '-oxopropyl)-5-fluorouracil (OFU001), which releases 5-fluorouracil upon hypoxic irradiation

Purpose: We previously proposed that a prodrug of 5-fluorouracil (5-FU), OF U001, is activated through capturing of hydrated electrons produced by hypo xic irradiation. Because hydrated electrons are readily deactivated by oxyg en, the 5-FU release occurs specifically upon hypoxic irradiation. In this study, we investigated the ira vivo efficacy, pharmacokinetics, and toxicit y of OFU001, Methods and Materials: Female 10-week-old C3H/He mice bearing SCCVII tumors were used. To measure release of 5-FU from OFU001 in vitro, the mice were given 100 mg/kg of OFU001 intraperitoneally and irradiated. Thereafter, 5-F U levels in the tumor and serum were measured by high-performance liquid ch romatography. To evaluate in vivo efficacy, OFU001 was administered 30 min before irradiation, and radiation-potentiating effects were investigated by means of a tumor growth delay assay and a 50% tumor control dose (TCD-50) assay. The lethal dose of OFU001 was evaluated in the same mice. Results: Following administration of OFU001 and irradiation at 30 Gy, the a verage 5-FU levels in the tumor and serum were 179 ng/g and 83 ng/mL, respe ctively. Administration of OFU001 (100-200 mg/kg) to the tumor-bearing mice before a single dose of 15-Gy irradiation produced a mean tumor growth del ay of 1-5 days as compared to radiation alone (although the delay was not s ignificant), However, no additional growth delay was observed when OFU001 w as combined with 5 radiation fractions of 4 Gy each. The enhancement ratio of OFU001 in the TCD-50 assay was 1.2. No mice died after administration of 0.6-1.2 g/kg of OFU001, Conclusions: OFU001 appears to work iia vitro via the proposed mechanism of activation, Although the in vivo effect of this compound was not strong en ough for clinical efficacy, these results should encourage further research on the development of prodrugs of more potent anticancer agents activated through the same mechanism, (C) 2001 Elsevier Science Inc.