Cell cycle-dependent cytotoxicity and induction of apoptosis by liposomal N4-hexadecyl-1-beta-D-arabinofuranosylcytosine.
The clonogenic growth inhibition, the cell cycle dependence of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) cytotoxicity and the capability to induce apoptosis in ara-C-sensitive and -resistant HL-60 cells were investigated and compared with arabinofuranosylcytosine (ara-C). In the clonogenic assay with sensitive HL-60 cells, ara-C was slightly more effective than a liposomal preparation of NHAC, whereas in the resistant cells, NHAC revealed its potency to overcome ara-C resistance, resulting in a 23-fold lower 50% inhibitory concentration compared with ara-C. Cell cycle dependent cytotoxicity and induction of apoptosis were studied by flow cytometry, using the bromodeoxyuridine-propidium iodide and terminal transferase method respectively. In contrast to ara-C, NHAC exerted no phase-specific toxicity at low concentrations (< 40 microM). At higher concentrations the S-phase-specific toxicity increased, probably resulting from ara-C formed from NHAC. NHAC induced apoptosis at higher drug concentrations than ara-C, however apoptosis appeared not to be limited to the S-phase cells. Apoptosis occurred in both cell lines within 2-4 h after drug exposure. These results give further evidence that NHAC exerts its cytotoxicity by different mechanisms of action than ara-C and might therefore be active in ara-C-resistant tumours.
Horber
D H
DH
Department of Internal Medicine, Medical Oncology, University Hospital, Zürich, Switzerland.
von Ballmoos
P
P
Schott
H
H
Schwendener
R A
RA
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D016196:S Phase; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004337:Drug Carriers; D008081:Liposomes; D003561:Cytarabine; C074701:N(4)-hexadecyl-1-arabinofuranosylcytosine