Desferrioxamine enhances the effects of gamma radiation on clonogenic survival and the formation of chromosomal aberrations in endothelial cells.
Vascular injury and endothelial damage contribute to the efficacy and complications of radiotherapy. Iron chelation protects against iron-catalyzed oxidative injury, but it also inhibits DNA synthesis in proliferating cells and can cause apoptosis. We examined the prevailing effects of iron chelation on the survival of gamma-irradiated human umbilical vein endothelial cells by treating monolayers, primarily in the G1/G0 phase of the cell cycle, with the iron chelator desferrioxamine for 24 h prior to gamma irradiation. Desferrioxamine treatment alone diminished plating efficiency by inducing apoptosis and delaying proliferation; this effect disappeared by 48 h. Desferrioxamine treatment reduced clonogenic survival after exposure to 2.5 Gy gamma radiation, but neither iron loading with hemin nor treatment with another iron chelator, 2,2-dipyridyl, which is a potent inhibitor of ribonucleotide reductase, had an effect on survival after irradiation. Clonogenic survival and chromosomal aberrations were measured in parallel in endothelial cells treated with desferrioxamine after increasing doses of gamma radiation. In a linear-quadratic model of survival, desferrioxamine treatment did not change the occurrence of directly lethal lesions, but it significantly increased sublethal injury. Desferrioxamine was not clastogenic alone, but it increased the frequency of formation of chromosomal rings and of excess acentric fragments after gamma irradiation.
Juckett
M B
MB
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226, USA.
Shadley
J D
JD
Zheng
Y
Y
Klein
J P
JP
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D003676:Deferoxamine / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000528:radiation effects*; D005720:Gamma Rays; D006801:Humans; D007501:Iron / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology
D011838:Radiation-Sensitizing Agents; D007501:Iron; D003676:Deferoxamine