The combined application of DNA unwinding and strand-scission agents is a novel and potentially important approach to cancer therapy, based in part on mechanistic considerations of drug action. In order to evaluate this hypothesis a number of experiments were performed in which the cellular cytotoxicity of DNA reactive agents (ethidium bromide, adriamycin or cis-platinum) were evaluated alone and in combination with bleomycin, a strand-scission agent, using a number of different tumor cell systems in vitro. The results of these studies indicated that combinations of these agents were found to be much more effective than treatment with single drugs alone. This conclusion was warranted for the action of ethidium bromide followed by bleomycin with murine L1210 leukemia, melanoma B16-BL6 and human HeLa cells, and cis-platinum followed by bleomycin with L1210 and B16-BL6 cells. These data support previous findings in which synergistic growth inhibition of L1210 cells by ethidium bromide, followed by bleomycin was explained by a two-step mechanism; first, ethidium bromide introduces changes in DNA-conformati on resulting in the facilitation of a second step in which bleomycin cleaves DNA more efficiently. Therefore, the rational use of combinations of DNA reactive agents based on mechanistic considerations should result with improved therapeutic regimens for the treatment of cancer.
