In vitro cellular accumulation and cytotoxicity of liposomal and conventional formulations of daunorubicin and doxorubicin in resistant K562 cells

Previous investigations have indicated the possibility to circumvent multid rug resistance (MDR) by incorporation of an anthracycline into liposomes, W e examined the in vitro cytotoxicity and cellular drug accumulation of the anthracyclines daunorubicin and doxorubicin compared with the commercially available liposomal formulations DaunoXome(R) and Caelyx(R) in human myelog enous leukemia K562 cells, The drug-sensitive parental K562/K line was comp ared with the P-glykoprotein (P-gp)-expressing cell lines K562/Dnr and K562 /Vcr. Two cell lines with reduced levels of topoisomerase II (K562/Nov and K562/Ida) were also included. The cytotoxicity was determined by fluorometr ic microculture cytotoxicity assay and the cellular drug levels were determ ined by high performance liquid chromatograghy, There was a strong inverse correlation between P-gp levels and celluar drug accumulation (rho= - 0.83, p= 0.04) and cytotoxicity (rho=-0.95, p=0.01) of daunorubicin, Also the cy totoxicity of DaunoXome and doxorubicin was related to P-gp levels (rho=-0. 96, p=0.01 and rho=-0.90, p=0.07, respectively). Caelyx did not show any cy totoxic effect due to impaired cellular uptake of the pegylated liposome, R egardless of the P-gp levels of the treated cells, DaunoXome showed the sam e cytotoxic effect despite lower intracellular accumulation (range 22-47%), compared with conventional daunorubicin. [(C) 1999 Lippincott Williams & W ilkins.].