FREE-RADICAL MODES OF CYTOTOXICITY OF ADRIAMYCIN(R) AND STREPTONIGRIN

Free radical modes of cytotoxicity of streptonigrin (STN) and Adriamyc in(R) (ADR) in Chinese hamster V79 cells under aerobic conditions were evaluated using 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TP), a low molecular weight stable nitroxide free radical with antioxidant properties and desferrioxamine (DF), a transition metal chelator. In a ddition, exogenous superoxide dismutase (SOD, EC 1.15.1.1) and catalas e (CAT, EC 1.11.1.6), were tested for cytoprotective effects. EPR stud ies showed that TP reacts with the semiquinones of both ADR and STN an d also with O-2(-) radicals generated during aerobic redox cycling of the respective semiquinone radicals. Pulsed field gel electrophoresis studies confirmed that DNA double-strand breaks (dsb) induced by STN i n V79 cells were inhibited completely by TP, whereas ADR-induced DNA d sb were not affected by TP. Clonogenic cell survival studies showed th at STN-induced cytotoxicity could be inhibited completely by DF or TP. Both agents were ineffective in inhibiting ADR-induced cytotoxicity. SOD and CAT were ineffective in protecting against both STN and ADR cy totoxicity. Our results are consistent with a mechanism requiring the semiquinone radical intermediate of STN for cytotoxicity and minimal f ree radical involvement in ADR-induced V79 cell cytotoxicity.