title: A fluorinated 2-nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer.
abstract: To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-nitroimidazole. Of the resulting compounds, KU-2285 (a 2-nitroimidazole with an N1-substituent of CH2CF2CONHCH2-CH2OH) was considered the most useful as a hypoxic cell radiosensitizer. In this study, its in vivo radiosensitizing activity and acute toxicity were compared with those of etanidazole. The reduction potentials of KU-2285 and etanidazole were -0.96 V and -1.05 V vs Ag/Ag+ in N,N-dimethylformamide, respectively, and their respective octanol/water partition coefficients were 0.25 and 0.040. The in vivo radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose when assayed by an in vivo-in vitro assay, a growth delay assay, and a tumor control assay using SCC VII tumor or transplanted mammary tumor in C3H/He mice. Although the radiosensitizing activity of etanidazole was reduced when it was administered orally, there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. The acute toxicity measured as the LD50/7 in 8-week-old female C3H/HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole.
authors.affiliation: Department of Radiology, Faculty of Medicine, Kyoto University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sasai
authors.forename: S
authors.initials: S
authors.lastname: Nishimoto
authors.forename: K
authors.initials: K
authors.lastname: Shimokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hisanaga
authors.forename: Y
authors.initials: Y
authors.lastname: Kitakabu
authors.forename: Y
authors.initials: Y
authors.lastname: Shibamoto
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Kagiya
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D017341:Etanidazole; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D009593:Nitroimidazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C069296:KU 2285; D017341:Etanidazole