In vitro toxicological evaluation of ISIS 1082, a phosphorothioate oligonucleotide inhibitor of herpes simplex virus.
ISIS 1082, a phosphorothioate oligonucleotide targeted to a translation initiation codon of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) virion capsid protein UL13 inhibits in vitro viral replication. To better understand the pharmacological properties of ISIS 1082, we examined its effects in nonvirally infected HeLa cells by using a number of cytotoxicity assays. Our data indicate that ISIS 1082 had no effect on HeLa cell viability as measured by cellular proliferation and clonogenic assays at concentrations as high as 100 microM. Additionally, DNA, RNA, and protein synthesis were only inhibited by 25% in cells treated with 100 microM ISIS 1082. The effects of ISIS 1082 on DNA synthesis were compared with those of acyclovir and trifluorothymidine, two clinically used antiherpetic agents. Acyclovir displayed effects similar to that of ISIS 1082. However, trifluorothymidine, which has been reported to be a potential mutagen and teratogen, significantly altered DNA replication at concentrations from 1 to 100 microM. Isolated HeLa DNA polymerases were inhibited by the compound, with a 50% inhibitory concentration of 2 microM. The in vitro antiviral (K. Draper and V. Brown-Driver, submitted for publication; K.G. Draper and V. Brown-Driver, Antiviral Res. Suppl. 1:106, 1991) and cytotoxicity studies suggest that ISIS 1082 is a selective, nontoxic, antiherpetic therapeutic agent.
Crooke
R M
RM
ISIS Pharmaceuticals, Carlsbad, California 92008.
Hoke
G D
GD
Shoemaker
J E
JE
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis; D018139:Simplexvirus / Q000187:drug effects*; D013873:Thionucleotides / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D000998:Antiviral Agents; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; D013873:Thionucleotides; C075374:ISIS 1082; D012313:RNA; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D013936:Thymidine