Novel enzymatic and immunological responses to oligonucleotides.
Oligonucleotide phosphorothioates (PS-oligos) are being studied as antisense agents for viral infection and cancer. In preclinical studies, PS-oligos produced dose-dependent changes in heart rate and blood pressure and significantly reduced serum hemolytic complement, which could be avoided by slowing infusion rates. Here, in vitro PS-oligo treatment of either human, rhesus monkey or guinea pig serum reduced hemolytic complement and further inhibited in vitro coagulation when added to whole blood or citrated plasma. These effects were dependent upon both oligonucleotide dose and structure. Oligonucleotides having identical sequences but containing methylphosphonates (Chimeric), 2'-O-methyl ribonucleosides (Hybrid) or 3' hairpin loop (Self-stabilized) had altered effects on complement and coagulation in vitro.
Agrawal
S
S
Hybridon, Inc., Worcester, MA 01605, USA.
Rustagi
P K
PK
Shaw
D R
DR
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003165:Complement System Proteins / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D008253:Macaca mulatta; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000494:pharmacology*
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D003165:Complement System Proteins