Copper chelator enhancement of bleomycin cytotoxicity

Bleomycin's effects on DNA strand scission are inhibited by low concentration of some metal ions (including copper), greatly stimulated by ferrous (Fe+2) ions, and increased and probably mediated by the production of superoxide radicals (O2-), hydroxyl radicals (OH), and hydrogen peroxide (H2O2). However, the role of these mechanisms in overall bleomycin cytotoxicity is not known. For this reason, we have treated the Chinese hamster cell line (V79) cells with a copper chelator, diethyldithiocarbamate (DDC) and bleomycin in vitro DDC is known to inhibit superoxide dismutase (SOD), an enzyme responsible for the scavenging of O2-. The cytotoxicity is determined by the standard clonogenic survival method, which shows that DDC treated cells are more susceptible to bleomycin either as a function of bleomycin dose or as a function of bleomycin treatment time. These results support the notion that reducing Cu2+ levels and/or increasing O2- concentrations can modify the cytotoxicity of bleomycin.