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Comparison of Adriamycin- and Ouabain-induced Cytotoxicity and Inhibition of ⁸⁶Rubidium Transport in Wild-Type and Ouabainresistant C3H/10T1/2 Mouse Fibroblasts¹

Cancer Research Laboratory, University of Southern California Comprehensive Cancer Center [J. R. L., R. S. B., C. H.], and Los Angeles County General Hospital [N. T.], Los Angeles, California 90033

Ouabain (OUA) inhibited ⁸⁶Rb uptake (50% inhibitory concentration = 0.8 x 10^-4 M) over concentration ranges close to those at which it caused a reversible cytotoxicity (50% lethal dose = 2.5 x 10^-4 M) in growing wild-type C3H/10T1/2 cells. On the other hand, Adriamycin (ADM) inhibited ⁸⁶Rb uptake (50% inhibitory concentration = 2 x 10^-3 M) but at concentrations 10⁴-fold higher than those causing irreversible cytotoxicity in growing wild-type cells (50% lethal dose = 3 x 10^-8 M). While OUA inhibited ⁸⁶Rb uptake more in wild-type cells than in a OUA-resistant mutant, ADM inhibited ⁸⁶Rb uptake to the same extent in confluent wild-type and OUA-resistant cells. Further, 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. In addition, 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).

Therefore, in this model system, ADM cytotoxicity is mediated differently from OUA cytotoxicity. Further, we find no biological evidence consistent with ADM binding to the OUA site on the cell surface (Na⁺-K⁺) adenosine triphosphatase and therefore no evidence in this model system that ADM cardiotoxicity could be a digitalis-type toxicity per se.

¹ This work was supported by the Robert E. and May R. Wright Foundation, by Grant CA-21036 from the National Cancer Institute, NIH, and by Grant BC-2H from the American Cancer Society.

² Recipient of American Cancer Society Postdoctoral Fellowship Grant PF-1331. To whom requests for reprints should be addressed.

³ Present address: City of Hope Hospital, Duarte, Calif.

Received 4/28/80. Accepted 9/11/80.

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