Synergistic interactions of ethidium bromide and bleomycin on cellular DNA and growth inhibition

Bleomycin is an anti-tumor agent whose cytotoxicity is related to the introduction of both single-stranded and double-stranded breaks in cellular DNA. In an assay using isolated nuclei, low levels of ethidium bromide substantially increased bleomycin induced release of nuclear chromatin. Treatment of mouse L1210 leukemia cells in vitro with low levels of ethidium bromide followed 1 hr later by bleomycin produced a synergistic effect that was 8 fold greater than that expected from the additive cytotoxicity of each drug alone. Interestingly, when the order of drug addition was reversed the drug synergism was much reduced (2 fold). The combination of DNA unwinding and strand scission agents may represent a novel and rational approach to the chemotherapy of cancer.