Decreased retention of actinomycin D as the basis for cross-resistance in anthracycline-resistant sublines of P388 leukemia.
Sublines of P388 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-hr exposure in vitro and 370-fold resistant when exposed to the drug for 16 hr. The immediate binding of radioactive actinomycin D to sensitive and resistant cells was similar, and the uptake of the drug by the 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 either Tween 80 or acridine orange incresed 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. It is concluded that these tumors must retain appreciable concentrations of actinomycin D for several hr in order to be killed. The anthracycline-resistant sublines are cross-resistant to actinomycin D by virtue of their inability to retain the drug.
D000166:Acridines / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003609:Dactinomycin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011136:Polysorbates / Q000494:pharmacology
D000166:Acridines; D008081:Liposomes; D011136:Polysorbates; D003609:Dactinomycin; D004317:Doxorubicin; D003630:Daunorubicin