Hypoxia-specific targeting of a repair inhibitor

A novel conjugale (NITP) between a 2-nitroimidazole and theophylline had a similar hypoxic-cell radiosensitizing efficiency to misonidazole, with no effect on the radiosensitivity of well oxygenated cells. If the cells were incubated with the drug under aerobic conditions for 18 h after hypoxic, but not oxic, irradiation, the shoulder of the survival curve was reduced leading to an effective gain in radiosensitizing efficiency. No such effect of post-irradiation incubation was observed with the same concentrations of misonidazole. Although NITP was slightly more toxic, on a concentration basis, than misonidazole this might be offset in vivo by a reduced time-dependence of toxicity. Conjugation of a repair inhibitor and an electron-affinic radiosensitizer offers a promising route to improving the radiosensitizing efficiency of nitroimidazoles with the low doses used in fractionated radiotherapy. (author)