The mononucleotide-dependent, nonantisense mechanism of action of phosphodiester and phosphorothioate oligonucleotides depends upon the activity of an ecto-5′-nucleotidase

• Published in: Blood 2001-08, Vol.98 (4), p.995-1002
• Main Authors: Koziolkiewicz, Maria, Gendaszewska, Edyta, Maszewska, Maria, Stein, C.A., Stec, Wojciech J.
• Format: Article
• Language: English
• Subjects: 5'-Nucleotidase - metabolism; Antineoplastic agents; Biological and medical sciences; Carrier Proteins - pharmacology; Carrier Proteins - physiology; Cell Division - drug effects; Deoxyribonucleotides - chemical synthesis; Deoxyribonucleotides - pharmacokinetics; Deoxyribonucleotides - pharmacology; Dose-Response Relationship, Drug; Endothelium, Vascular - cytology; General aspects; HL-60 Cells; Humans; Kinetics; Medical sciences; Membrane Proteins - pharmacology; Membrane Proteins - physiology; Nucleoside Transport Proteins; Oligodeoxyribonucleotides - chemical synthesis; Oligodeoxyribonucleotides - pharmacokinetics; Oligodeoxyribonucleotides - pharmacology; Oligodeoxyribonucleotides, Antisense - chemical synthesis; Oligodeoxyribonucleotides, Antisense - pharmacokinetics; Oligodeoxyribonucleotides, Antisense - pharmacology; Organothiophosphorus Compounds - chemical synthesis; Organothiophosphorus Compounds - pharmacology; Pharmacology. Drug treatments; Thionucleotides - chemical synthesis; Thionucleotides - pharmacokinetics; Thionucleotides - pharmacology; Tumor Cells, Cultured; Umbilical Cord - cytology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V98.4.995

Many reports indicate different nonantisense yet sequence-specific effects of antisense phosphorothioate oligonucleotides. Products of enzymatic degradation of the oligonucleotides can also influence cell proliferation. The cytotoxic effects of deoxyribonucleoside-5′-phosphates (dNMPs) and their 5′-phosphorothioate analogs, deoxyribonucleoside-5′-monophosphorothioates (dNMPSs) on 4 human cell types (HeLa, HL-60, K-562, and endothelial cells) were examined, and the effects were correlated with the catabolism of these compounds. The results indicate that differences in cytotoxicity of dNMPs or dNMPSs in these cells depend upon different activity of an ecto-5′-nucleotidase. It has also been found that dNMPSs stimulate proliferation of human umbilical vein endothelial cells and HL-60 cells in a concentration-dependent manner. This stimulation might be caused by the binding of deoxynucleoside-5′-phosphorothioates to as-yet unidentified nucleotide receptor(s) at the cell surface.