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The Use of Zn-Desferrioxamine for Radioprotection in Mice, Tissue Culture, and Isolated DNA¹

Radiation Biology Branch [D. C., A. M. D., W. G. D., J. B. M.] and Biostatistics and Data Management section [D. J. V.], Division of Clinical Sciences, National Cancer Institute, and Secretory Physiology Section, Gene Therapy and Therapeutics Branch [I. A.], Division of Intramural Research, National Institute of Dental Research, NIH, Bethesda, Maryland 20892, and Cellular Biochemistry, Schools of Medicine and Dentistry, Hebrew University, Jerusalem 91120, Israel [Y. S., M. C.]

Redox-active metals mediate oxidative injury and might also potentiate radiation damage. The iron chelator desferrioxamine (DFO), which diminishes oxidative damage in many chemical and biological systems as well as in human subjects, has a controversial role in radiobiology and reportedly acts both as a radiosensitizer and a radioprotector. The present research focused on the radioprotective activity of its zinc complex. Zn-DFO was studied using three 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 mM) protected isolated DNA against -radiation better than each of its components alone; however, neither Zn-DFO nor DFO (50–100 µM) alone affected the radiation sensitivity of cultured cells. With total body irradiation, Zn-DFO, but not DFO alone at 100 µmol/kg body weight, administered to mice 30 min before irradiation provided significant radioprotection (P < 0.01). Zn-DFO had an LD_50/30 of 10.3 Gy, whereas DFO and vehicle alone had LD_50/30s of 8.03 Gy and 7.91 Gy, respectively. The effect of Zn-DFO on the hemodynamic parameters in mice did not differ from that of the vehicle (saline) alone. This excludes the explanation that the radioprotective activity of Zn-DFO results from its effect on oxygen levels. In addition to the possible direct effect of Zn, other potential modes of action underlying the radioprotective activity of Zn-DFO might involve a displacement of iron and its substitution by zinc, a greater proximity of the drug to DNA, and less likely an improved penetration of the drug into cells because of its structure. The failure of Zn-DFO to protect cells in tissue cultures indicates that it has some systemic role in the whole animal, possibly due to a prolonged half-life in the animal’s circulation.

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