A fluorinated 2-nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer

Int J Radiat Oncol Biol Phys. 1991 Jun;20(6):1249-54. doi: 10.1016/0360-3016(91)90235-v.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Combined Modality Therapy
  • Dose-Response Relationship, Radiation
  • Etanidazole
  • Female
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / radiotherapy
  • Nitroimidazoles / pharmacology*
  • Nitroimidazoles / therapeutic use
  • Nitroimidazoles / toxicity
  • Radiation-Sensitizing Agents / pharmacology*
  • Radiation-Sensitizing Agents / therapeutic use
  • Radiation-Sensitizing Agents / toxicity

Substances

  • Nitroimidazoles
  • Radiation-Sensitizing Agents
  • KU 2285
  • Etanidazole