Spin labeled antioxidants protect bacteria against the toxicity of alkylating antitumor drug CCNU.

We have studied the toxic effect of the alkylating antitumor drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU) on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) strains, alone and in presence of oxygen radical-scavenging substances [Vitamin E, stable nitroxyl radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TMPO), and spin labeled (nitroxyl free radical moiety containing) analogues of CCNU] and compared with that of the alkylating antitumor drug 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTIC). All spin labeled compounds tested were almost no toxic at doses of 50-500 microM/ml, whereas the alkylating antitumor drug CCNU showed toxicity in a dose dependent manner. Even low doses of spin labeled nitrosoureas provided protection against the toxicity caused by the antitumor drug CCNU alone. The lowest toxicity against E. coli and S. aureus were achieved when 500 microM/ml of CCNU was combined with 200 microM/ml of spin labeled nitrosourea N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-glycine amid of 2,2,6,6-tetramethyl-4-aminopiperidine-1-oxyl (SLCNUgly). A combination of TMPO with vitamin E completely abolished the toxicity of CCNU. Endogenous formation of oxygen radicals and their possible involvement in CCNU toxicity towards the bacteria strains tested have been also discussed.