Dh. Horber et al., CELL CYCLE-DEPENDENT CYTOTOXICITY AND INDUCTION OF APOPTOSIS BY LIPOSOMAL N-4-HEXADECYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE, British Journal of Cancer, 72(5), 1995, pp. 1067-1073
The clonogenic growth inhibition, the cell cycle dependence of N-4-hex
adecyl-1-beta-D-arabinofuranosylcytosine (NHAC) cytotoxicity and the c
apability to induce apoptosis in ara-C-sensitive and -resistant HL-60
cells were investigated and compared with arabinofuranosylcytosine (ar
a-C). In the clonogenic assay with sensitive HL-60 cells, ara-C was sl
ightly more effective than a liposomal preparation of NHAC, whereas in
the resistant cells, NHAC revealed its potency to overcome ara-C resi
stance, resulting in a 23-fold lower 50% inhibitory concentration comp
ared with ara-C. Cell cycle dependent cytotoxicity and induction of ap
optosis were studied by flow cytometry, using the bromodeoxyuridine-pr
opidium iodide and terminal transferase method respectively. In contra
st to ara-C, NHAC exerted no phase-specific toxicity at low concentrat
ions (< 40 mu M). At higher concentrations the S-phase-specific toxici
ty increased, probably resulting from ara-C formed from NHAC. NHAC ind
uced apoptosis at higher drug concentrations than ara-C, however apopt
osis appeared not to be limited to the S-phase cells. Apoptosis occurr
ed in both cell lines within 2-4 h after drug exposure. These results
give further evidence that NHAC exerts its cytotoxicity by different m
echanisms of action than ara-C and might therefore be active in ara-C-
resistant tumours.