CELLULAR PHARMACOLOGY OF N-4-HEXADECYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE IN THE HUMAN LEUKEMIC-CELL LINES K-562 AND U-937

The mechanisms of cytotoxicity, cellular drug uptake, intracellular dr ug distribution, cellular pharmacokinetics, formation of arabinofurano sylcytosine triphosphate (ara-CTP), and DNA incorporation of N-4-hexad ecyl-1-beta-D-arabinofuranosylcytosine (NHAC), a new lipophilic deriva tive of arabinofuranosylcytosine (ara-C) formulated in small unilamell ar liposomes, were determined in vitro in the human leukemic cell line s K-562 and U-937. Furthermore, the induction of erythroid differentia tion by NHAC was tested in K-562 cells. The cytotoxicity of NHAC in bo th cell lines was not influenced by the deoxycytidine (dCyd) concentra tion or the presence of the nucleoside-transport-blocking agent dipyri damole as demonstrated in coincubations with dCyd and/or dipyridamole, whereas in contrast, the cytotoxicity of ara-C was decreased additive ly by both drugs. As compared with ara-C, the uptake of NHAC displayed up to 16- and 5-fold increases in K-562 and U-937 cells, respectively , depending on the drug concentration. Studies of the drug distributio n and pharmacokinetics of NHAC revealed a depot effect for NHAC in the cell membranes, resulting in half-lives 2.6 and 1.4 times longer than those of ara-C in the two cell lines. The ara-CTP concentrations deri ved from NHAC were 150- and 75-fold lower at a drug concentration of 1 mu M in K-562 and U-937 cells, respectively. The DNA incorporation of the drugs observed after incubation with 2 mu M NHAC was 60- and 30-f old lower as compared with that seen at 2 mu M ara-C in the two cell l ines. Furthermore, NHAC was capable of inducing irreversible erythroid differentiation to a maximum of only 22% of K-562 cells, whereas ara- C induced differentiation at a drug concentration 100-fold lower in 50 % of the cells. These results indicate a mechanism of cytotoxicity for NHAC that is independent of the nucleoside transport mechanism and th e phosphorylation pathway and suggest that the mechanisms of action of NHAC are significantly different from those of ara-C. Therefore, NHAC might be used for the treatment of ara-C-resistant malignancies.