Ornithine decarboxylase (ODC) activity is induced when epidermal cells are incubated for 5-12 hr in the presence of 10 mum-adriamycin (ADR). The magnitude and duration of ODC induction by 5 mum-daunomycin (DAU) are much smaller. At 10 mum, ADR does not alter DNA synthesis but DAU inhibits ODC activity and DNA synthesis by 40 and 60%, respectively. ADR (10 mum) and, to a lesser degree, DAU (5 mum) also enhance 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity, but, in contrast to ADR, 10-50 mum-DAU inhibit the ODC response to TPA by 50% or more. The induction and superinduction of ODC activities by ADR and/or TPA are all inhibited by the Ca(2+)-channel blocker verapamil. The ODC-inducing activity of ADR, therefore, may have a role in the mechanism by which mouse epidermal cells escape from the cytotoxic activity of this anthracycline antibiotic.