In vivo toxicological effects of rel A antisense phosphorothioates in CD-1 mice.
To characterize the in vivo toxicity of phosphorothioate antisense oligonucleotides against rel A (p65 subunit of NF-kappa B transcription factor), forty-eight 6-week-old CD-1 mice were split into 4 groups (6/sex/group) receiving vehicle (phosphate-buffered saline) or doses of 50, 100, and 150 mg/kg of rel A antisense oligonucleotides intraperitoneally 3 times weekly for 2 weeks. Clinical signs of toxicity included weakness, and decreased motor activity and food consumption with body weight loss. Mortality occurred in 7 of 12 mice in the 150-mg/kg group and in 2 of 12 mice in the 100-mg/kg group, most of which died within the first 2 to 4 days of treatment. The remaining mice were necropsied on day 15. The major hematological finding was severe dose-dependent thrombocytopenia. The liver enzyme levels were mildly elevated in the serum of mid- and high-dose animals. At necropsy, increased spleen and liver weights were observed in treated mice, some of which also had mild pleural and/or peritoneal effusions. Histopathological examination revealed the likely cause of death to be acute renal failure due to renal cortical or tubular necrosis. Treatment-related changes were also found in the liver, spleen, bone marrow, and several other organs. In summary, the kidney, liver, and bone marrow (megakaryocytic lineage) were identified as the major target organs for toxicity with rel A antisense therapy.
Sarmiento
U M
UM
Department of Investigative Toxicology, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110.
Perez
J R
JR
Becker
J M
JM
Narayanan
R
R
D000818:Animals; D001483:Base Sequence; D005260:Female; D006403:Hematologic Tests; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D012016:Reference Values; D013873:Thionucleotides / Q000633:toxicity*
D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides