Calmodulin antagonist W 13 prevents DNA repair after bleomycin treatment of human urological tumor cells growing on extracellular matrix.

1. The combined application of DNA strand-scission agents (bleomycin) and inhibitors of recovery from lethal damage (calmodulin antagonist W-13) could be a novel and potentially important approach to cancer therapy. 2. As determined by alkaline elution, both DNA-DNA and DNA-protein cross-links in bleomycin-treated cells were revealed by the presence of the proteinase K assay. 3. This lethal effect could be potentiated by the addition of calmodulin antagonist W-13 that prevents the repair of DNA strand breaks and DNA cross-links caused by bleomycin. 4. The results indicated that combinations of bleomycin and W-13 were more effective than treatment with either single agent. Isobologram analysis suggests synergistic effect of these drugs. 5. Therefore, the rational use of combinations of DNA-strand-scission agents and inhibitors of recovery from lethal damage based on mechanistic considerations should result with improved therapeutic regimens for the treatment of cancer.