COMPARISON OF ADRIAMYCIN-INDUCED AND OUABAIN-INDUCED CYTO-TOXICITY AND INHIBITION OF RB-86 TRANSPORT IN WILD-TYPE AND OUABAIN-RESISTANT C3H-10T1/2 MOUSE FIBROBLASTS

Abstract

Ouabain (OUA, an antineoplastic drug) inhibited 86Rb uptake (50% inhibitory concentration [IC50] = 0.8 .times. 10-4 M) over concentration ranges close to those at which it caused a reversible cytotoxicity (LD50 = 2.5 .times. 10-4 M) in growing wild-type C3H/10T1/2 cells. Adriamycin (ADM, an antineoplastic drug) inhibited 86Rb uptake (IC50 = 2 .times. 10-3 M) but at concentrations 104-fold higher than those causing irreversible cytotoxicity in growing wild-type cells (LD50 = 3 .times. 10-8 M). OUA inhibited 86Rb uptake more in wild-type cells than in an OUA-resistant mutant; ADM inhibited 86Rb uptake to the same extent in confluent wild-type and OUA-resistant cells. Three OUA-resistant mutants were not cross-resistant to ADM- or daunomycin (DM)-induced cytotoxicity during log phase or to ADM- induced cytotoxicity at confluence. ADM, DM or 5-iminodaunomycin did not displace the cardiac glycosides digoxin or digitoxin from their respective antibody complexes. The order of potency of anthracycline derivatives in inhibiting 86Rb uptake in confluent wild-type cells was the same as their order of inhibiting the growth of wild-type cells and in detaching confluent wild-type cells (DM > ADM > 5-iminodaunomycin), but did not correlate with their cardiotoxic potentials (ADM > DM > 5-iminodaunomycin). In the model system, ADM cytotoxicity is mediated differently from OUA cytoxicity is mediated differently from OUA cytoxicity. No biological evidence consistent with ADM binding to the OUA site on the cell surface (Na+-K+) ATP and no evidence in this model system that ADM cardiotoxicity could be a digitalis-type toxicity per se was found.