MODULATION OF STREPTONIGRIN CYTOTOXICITY BY NITROXIDE SOD MIMICS

Nitroxides are cell-permeable, stable radicals that react readily with paramagnetic species such as transition metals or short-lived free ra dicals, though not generally with diamagnetic molecules. Nitroxides ca n undergo one-electron selective redox reactions and thereby potential ly modify the activity of cytotoxic drugs. Streptonigrin (SN) toxicity requires bioreduction to yield the semiquinone radical, and the toxic ity is reportedly mediated by transition metals and oxygen-derived rea ctive species via redox-cycling of the semiquinone intermediate. The p resent study shows that (1) nitroxides protected isolated DNA and also aerated or hypoxic bacterial cells from SN toxicity; (2) H2O2 potenti ated the hypoxic cytotoxicity of the drug but inhibited the damage to aerated cells; (3) pretreatment of cells with H2O2 conferred some prot ection, but not when the drug alone was preexposed to H2O2; and (4) de sferrioxamine and 2,2-dipyridyl, though neither diethylenetriamino pen taacetate, exogenous catalase, or superoxide dismutase, decreased SN-i nduced cell killing. The mechanisms by which nitroxides protect from S N toxicity involve both a selective radical-radical reaction with SN s emiquinone and the reoxidation of reduced cellular transition metal io ns. On the other hand, H2O2 appears to exert two opposing effects: (1) facilitation of cell killing by the Fenton reaction and (2) lowering the cellular level of reducing equivalents, thus inhibiting the biored uctive activation of SN.