Cellular pharmacology and protein binding of phosphoromonothioate and phosphorodithioate oligodeoxynucleotides: a comparative study.
Phosphorodithioate (PS2) oligodeoxynucleotides (oligos) represent a relatively new class of backbone-modified oligo that have potential use as antisense agents. PS2 oligos are isoelectronic with phosphodiester (PO) and phosphoromonothioate (PS) oligos, and are nuclease resistant. However, unlike their PS congeners, PS2 oligos do not contain chiral centers. Little is known about the manner in which PS2 oligos interact with biological systems. In this study, we compare the cellular pharmacology of PS and PS2 oligos in HL60 cells. Cell surface binding, internalization, and compartmentalization are examined. Furthermore, the ability of PS and PS2 oligos to bind to rsCD4 and bFGF and to inhibit the activity of protein kinase C (PKC) is examined. Although the behavior of PS2 oligos closely parallels that of PS oligos, PS2 oligos appear to interact with some biological systems in a slightly different manner than PS oligos. These results indicate that PS2 oligos may have therapeutic potential other than as antisense agents.
Tonkinson
J L
JL
Department of Medicine, Columbia University, New York, New York 10032.
Guvakova
M
M
Khaled
Z
Z
Lee
J
J
Yakubov
L
L
Marshall
W S
WS
Caruthers
M H
MH
Stein
C A
CA
D016475:3T3 Cells; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002451:Cell Compartmentation / Q000502:physiology; D002460:Cell Line; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D018950:Lipopolysaccharide Receptors; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D013873:Thionucleotides / Q000378:metabolism / Q000494:pharmacology*
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D007457:Iodine Radioisotopes; D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors; D016376:Oligonucleotides, Antisense; D011994:Recombinant Proteins; D013873:Thionucleotides; D016222:Fibroblast Growth Factor 2; D011493:Protein Kinase C