DECREASED RETENTION OF ACTINOMYCIN-D AS BASIS FOR CROSS-RESISTANCE IN ANTHRACYCLINE-RESISTANT SUBLINES OF P388 LEUKEMIA

Abstract

Sublines of P388 mouse leukemia resistant to adriamycin and daunorubicin were cross-resistant to actinomycin D in vivo and in vitro. The adriamycin-resistant cell line was 1000-fold resistant to actinomycin D on 1 h exposure in vitro and 370-fold resistant when exposed to the drug for 16 h. The immediate binding of radioactive actinomycin D to sensitive and resistant cells was similar, and the uptake of the drug by resistant cells was only about 27% less than the rate of uptake by sensitive cells. There was a dramatic difference in efflux of drug from sensitive and resistant sublines. Equivalent cytotoxicity of actinomycin D for the sensitive and resistant sublines was obtained at concentrations of the drug that resulted in approximately equivalent levels of net retention of actinomycin D (retained drug minus background levels of immediate binding of the drug to the cells). Incubation of cells in the presence of actinomycin D plus Tween 80 or acridine orange increased the rate of uptake and the percentage of actinomycin D retained by the resistant cells on short-term assays but did not reverse the resistance. These tumors must retain appreciable concentrations of actinomycin D for several hours to be killed. The anthracycline-resistant sublines are cross-resistant to actinomycin D by virtue of their inability to retain the drug.