In vivo evaluation of a novel antitumor prodrug, 1-(2'-oxopropyl)-5-fluorouracil (OFU001), which releases 5-fluorouracil upon hypoxic irradiation.
OBJECTIVE
We previously proposed that a prodrug of 5-fluorouracil (5-FU), OFU001, is activated through capturing of hydrated electrons produced by hypoxic irradiation. Because hydrated electrons are readily deactivated by oxygen, the 5-FU release occurs specifically upon hypoxic irradiation. In this study, we investigated the in vivo efficacy, pharmacokinetics, and toxicity of OFU001.


METHODS
Female 10-week-old C3H/He mice bearing SCCVII tumors were used. To measure release of 5-FU from OFU001 in vivo, the mice were given 100 mg/kg of OFU001 intraperitoneally and irradiated. Thereafter, 5-FU levels in the tumor and serum were measured by high-performance liquid chromatography. 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 average 5-FU levels in the tumor and serum were 179 ng/g and 83 ng/mL, respectively. 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 delay of 1-5 days as compared to radiation alone (although the delay was not significant). However, no additional growth delay was observed when OFU001 was 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 in vivo via the proposed mechanism of activation. Although the in vivo effect of this compound was not strong enough for clinical efficacy, these results should encourage further research on the development of prodrugs of more potent anticancer agents activated through the same mechanism.
Shibamoto
Y
Y
Department of Oncology, Institute for Frontier Medical Sciences;, Kyoto, Japan. yuta@frontier.kyoto-u.ac.jp
Zhou
L
L
Hatta
H
H
Mori
M
M
Nishimoto
S I
SI
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C410182:OFU 001; D011355:Prodrugs; D005472:Fluorouracil