The use of Zn-desferrioxamine for radioprotection in mice, tissue culture,and isolated DNA

Redox-active metals mediate oxidative injury and might also potentiate radi ation damage, The iron chelator desferrioxamine (DFO), which diminishes oxi dative damage in many chemical and biological systems as web as in human su bjects, has a controversial role in radiobiology and reportedly acts both a s a radiosensitizer and a radioprotector. The present research focused on t he radioprotective activity of its zinc complex, Zn-DFO was studied using t hree test systems differing by their complexities: isolated DNA from pUC 19 plasmid, cultured V79 Chinese hamster cells, and C3H mice. Zn-DFO (0.5-2 m M) protected isolated DNA against gamma-radiation better than each of its c omponents alone; however, neither Zn-DFO nor DFO (50-100 mu M) alone affect ed the radiation sensitivity of cultured cells. With total body irradiation , Zn-DFO, but not DFO alone at 100 mu mol/kg body weight, administered to m ice 30 min before irradiation provided significant radioprotection (P < 0.0 1). Zn-DFO had an LD50/30 of 10.3 Gy, whereas DFO and vehicle alone had LD( 50/30)s of 8.03 Gy and 7.91 Gy, respectively, The effect of Zn-DFO on the h emodynamic parameters in mice did not differ from that of the vehicle (sali ne) alone, This excludes the explanation that the radioprotective activity of Zn-DFO results from its effect on oxygen levels. In addition to the poss ible direct effect of Zn, other potential modes of action underlying the ra dioprotective activity of Zn-DFO might involve a displacement of iron and i ts substitution by zinc, a greater proximity of the drug to DNA, and less L ikely an improved penetration of the drug into cells because of its structu re. The failure of Zn-DFO to protect cells in tissue cultures indicates tha t it has some systemic role in the whole animal, possibly due to a prolonge d half-life in the animal's circulation.