Characteristics of uptake and cytotoxicity of a low-density lipoprotein-daunomycin complex in P388 leukemic cells.
We have investigated the in vitro drug-cell interaction and therapeutic effects of a low-density lipoprotein (LDL)-daunomycin complex as compared to free daunomycin. Uptake and retention of daunomycin were significantly enhanced in sensitive and resistant P388 leukemia cells when they were perfused with LDL-daunomycin complex relative to free drug. The interaction of the LDL-daunomycin complex with P388 cells appeared to be through a LDL-specific pathway since competition with free LDL but not high-density lipoprotein significantly reduced daunomycin uptake. The LDL-daunomycin complex was cytotoxic to both daunomycin-sensitive and daunomycin-resistant P388 sublines. Colony growth studies showed the LDL-daunomycin complex to be more cytotoxic at shorter exposure times relative to free drug. Resistant cells showed 55 and 12% colony growth with 10-min and 2-hr exposures, respectively, to 0.4 microgram daunomycin/ml of the LDL-daunomycin complex. Free drug at 0.4 microgram/ml drug concentration and similar exposure times resulted in no loss in colony growth. The resistant cells were subjected to cell cycle analysis based on DNA content and showed an accumulation of cells at the G2-M phase of the cell cycle when treated with the LDL-daunomycin complex, with no effects being observed with free daunomycin.
D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism* / Q000633:toxicity; D004351:Drug Resistance; D007700:Kinetics; D007941:Leukemia P388 / Q000503:physiopathology*; D007942:Leukemia, Experimental / Q000503:physiopathology*; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D003630:Daunorubicin