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

Autor: Horber, Daniel H., Cattaneo-Pangrazzi, Rosanna M. C., von Ballmoos, Prisca, Schott, Herbert, Ludwig, Peter S., Eriksson, Staffan, Fichtner, Iduna, Schwendener, Reto A.
Zdroj: Journal of Cancer Research and Clinical Oncology; 20000516, Vol. 126 Issue: 6 p311-319, 9p
Abstrakt: Abstract: The arabinofuranosylcytosine (AraC) derivative N 4-octadecyl-1-β-D-arabinofuranosylcytosine (NOAC) and its (5′ → 5′)-heterodinucleoside phosphate analog NOAC-AraC were compared with AraC for cytotoxicity, cell-cycle dependence, phosphorylation by deoxycytidine (dC) kinase and apoptosis induction 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 NOAC-AraC or AraC. In contrast to NOAC-AraC, the lipophilic monomer NOAC overcame AraC resistance, inducing apoptosis in more than 80% of native and AraC-resistant HL-60 cells. This suggests that NOAC-AraC may be cleaved intracellularly only at very slow rates to AraC and NOAC or to the 5′-monophosphates, 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 with alkyl chains ranging from 6–18 C atoms were not substrates for dC kinase. Furthermore, treatment of the multidrug-resistant cell lines KB-ChR-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 are able to circumvent MDR1 multidrug resistance. The in vivo activity of liposomal NOAC in a human acute lymphatic leukemia xenograft model confirmed the antitumor activity of this representative of the N 4-alkyl-arabinofuranosylcytosines.
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