Cytotoxicity, cell-cycle perturbations and apoptosis in human tumor cells by lipophilic N4-alkyl-1-beta-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5'-->5')-N4-octadecyl-1-beta-D-arabinofuranosylcytosi ne.
The arabinofuranosylcytosine (AraC) derivative N4-octadecyl-1-beta-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, N4-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 N4-hexadecyl-AraC derivative NHAC did not induce P-170 glycoprotein expression, suggesting that the N4-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 N4-alkyl-arabinofuranosylcytosines.
Horber
D H
DH
Department of Pathology, University Hospital Zürich, Switzerland.
Cattaneo-Pangrazzi
R M
RM
von Ballmoos
P
P
Schott
H
H
Ludwig
P S
PS
Eriksson
S
S
Fichtner
I
I
Schwendener
R A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019281:Dimerization; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D014183:Transplantation, Heterologous
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D010710:Phosphates; D011355:Prodrugs; D003561:Cytarabine; C065145:N(4)-oleylcytosine arabinoside; D003842:Deoxycytidine Kinase