Radioprotection by DNA ligands.

Molecular studies on the mechanism of radioprotection by Hoechst 33342 have suggested that radioprotective activity might be improved by addition of electron-donating substituents to the ligand. This paper reports the results of experiments with proamine, in which the ethoxy group of Hoechst 33342 has been replaced with a dimethylamino group. Clonogenic survival studies with V79 cells confirmed the expectation of increased radioprotective activity of proamine. Also, proamine is less cytotoxic than Hoechst 33342, which further improves the extent of achievable radioprotection. The more general features of DNA-binding radioprotectors are also discussed in terms of their potential use in cancer radiotherapy. In particular it is proposed that the limited penetration of the compounds through cell layers might enable delivery to epithelial tissues by topical application, with limited access to the tumour via systemic uptake. In this context, the question of whether sufficient concentrations of such radioprotectors can be achieved in vivo has been addressed by experiments with the mouse lung model. In control animals, the ED50 for lethal loss of respiratory function at 16 weeks after irradiation was 19 Gy (single dose). Intravenous injection of Hoechst 33342 before irradiation extended the ED50 to 23 Gy.