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

Many reports indicate different nonantisense yet sequence-specific effects of antisense phosphorothioate oligonucleotides. Products of enzymatic degra dation of the oligonucleotides can also influence cell proliferation. The c ytotoxic effects of deoxyribonucleoside-5 ' -phosphates (dNMPs) and their 5 ' -phosphorothioate analogs, deoxyribonucleoside-5 ' -monophosphorothioate s (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 the se compounds. The results indicate that differences in cytotoxicity of dNMP s or dNMPSs in these cells depend upon different activity of an ecto-5 ' -n ucleotidase, It has also been found that dNMPSs stimulate proliferation of human umbilical vein endothelial cells and HL-60 cells in a concentration-d ependent manner. This stimulation might be caused by the binding of deoxynu cleoside-5 ' -phosphorothioates to as-yet unidentified nucleotide receptor( s) at the cell surface. (C) 2001 by The American Society of Hematology.