Cytotoxicity, cell-cycle perturbations and apoptosis in human tumor cells by lipophilic N-4-alkyl-1-beta-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5 '-> 5 ')-N-4-octadecyl-1-beta-D-arabinofuranosylcytosine

The arabinofuranosylcytosine (AraC) derivative N-4-octadecyl-1-beta-D-arabi nofuranosylcytosine (NOAC) and its (5' --> 5')-heterodinucleoside phosphate analog NOAC-AraC were compared with AraC for cytotoxicity, cell-cycle depe ndence, phosphorylation by deoxycytidine (dC) kinase and apoptosis inductio n in native, AraC- or NOAC-resistant HL-60 cells. NOAC was cytotoxic in all cells with three to seven-fold lower IC50 concentrations than those of NOA C-AraC or AraC. In contrast to NOAC-AraC, the lipophilic monomer NOAC overc ame AraC resistance, inducing apoptosis in more than 80% of native and AraC -resistant HL-60 cells. This suggests that NOAC-AraC may be cleaved intrace llularly only at very slow rates to AraC and NOAC or to the 5'-monophosphat es, whereas NOAC exerts different mechanisms of action from AraC. In vitro the dimer was cleaved by phosphodiesterase or human serum to NOAC, AraC and AraC monophosphate. In contrast to AraC, N-4-alkylated AraC derivatives wi th alkyl chains ranging from 6-18 C atoms were not substrates for dC kinase . Furthermore, treatment of the multidrug-resistant cell lines KB-Ch(R)-8-5 and KB-V1 with the N-4-hexadecyl-AraC derivative NHAC did not induce P-170 glycoprotein expression, suggesting that the N-4-alkyl-AraC derivatives ar e able to circumvent MDR1 multidrug resistance. The in vivo activity of lip osomal NOAC in a human acute lymphatic leukemia xenograft model confirmed t he antitumor activity of this representative of the N-4-alkyl-arabinofurano sylcytosines.