CELLULAR PHARMACOLOGY OF A LIPOSOMAL PREPARATION OF N-4-HEXADECYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE, A LIPOPHILIC DERIVATIVE OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE

The in vitro deamination, cytotoxicity, cellular drug uptake, distribu tion and cellular pharmacology in HL-60 cells of N-4-hexadecyl-1-beta- D-arabinofuranosylcytosine (NHAC), a lipophilic derivative of arabinof uranosylcytosine (ara-C), were studied. Compared with ara-C, NHAC in l iposomal formulations was highly resistant to deamination, resulting i n levels of formation of arabinofuranosyluracil 42 and ten times lower in plasma and liver microsomes respectively. The cytotoxicity of NHAC was independent of both the nucleoside transporter mechanism and the deoxycytidine (dCyd) kinase activity as demonstrated by co-incubating NHAC with dipyridamole and/or dCyd. In ara C-resistant HL-60 cells NHA C was still cytotoxic, requiring drug concentration only 1.6 times hig her than sensitive cells. Uptake of NHAC was six times higher and was not inhibited by dipyridamole. The pharmacokinetics of NHAC revealed t hat its intracellular half-life is 4.8 times longer than that of ara-C . Ara-CTP formation and incorporation into DNA was up to 25-50 times l ower than that of ara-C and contributed only marginally to the cytotox ic effects of NHAC. These results indicate that, because of the signif icantly increased stability, the transporter-independent uptake and th e dCyd-kinase-independent cytotoxicity, NHAC might be active in ara-C- resistant cells.