Abstract:
:ISIS 2302 is a phosphorothioate oligodeoxynucleotide with a sequence complementary to the mRNA of human intercellular adhesion molecule 1 (ICAM-1). Hybridization of ISIS 2302 to the mRNA inhibits expression of the ICAM-1 protein in response to inflammatory stimuli. A murine active antisense oligonucleotide, ISIS 3082, has been used for in vivo pharmacology studies and has anti-inflammatory activity in models of organ transplant rejection, ulcerative colitis, and collagen-induced arthritis at doses ranging from 0.03 to 5 mg/kg. The safety assessment for ISIS 2302 includes general toxicity studies up to 6 mo in duration in mice and monkeys, genetic toxicity studies, and reproductive/fertility studies. ISIS 3082 was examined in parallel with ISIS 2302 in mouse toxicity and reproductive studies. The toxicities observed following systemic administration of ISIS 2302 and ISIS 3082 were similar and consistent with those observed for other compounds in this chemical class and, therefore, are independent of the suppression of ICAM-1 expression. Toxicokinetic evaluation demonstrated that toxicities occurred in organs containing the highest concentrations of ISIS 2302. Evidence of immune stimulation. including dose-dependent splenomegaly, lymphoid hyperplasia, and multiorgan mixed mononuclear cell infiltrates, was the most common finding in rodent studies. Monkeys were much less sensitive than mice to immune stimulation. Kidney contained the highest concentrations of ISIS 2302. Morphologic changes observed in kidney included atrophic and regenerative changes in proximal tubular epithelium; however, there was no evidence of functional abnormalities. Additional histologic changes noted in proximal tubular epithelium included basophilic granules, which were reflective of oligonucleotide distribution and uptake in these cells. Liver also contained high concentrations of oligonucleotide, which were associated with Kupffer cell hypertrophy in mice. Changes in serum transaminases, cholesterol, and triglycerides were reflective of hepatic alterations. In monkeys, high concentrations of oligonucleotide caused a transient increase in clotting times and activation of the alternative complement pathway. All toxicities associated with ISIS 2302 were reversible and occurred at doses well above those required for pharmacologic activity or currently used in clinical trials. In addition, there has been no evidence of genetic toxicity associated with ISIS 2302, and no changes in reproductive performance, fertility, or fetal development have been noted in animals treated with ISIS 2302 or ISIS 3082.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Henry SP,Templin MV,Gillett N,Rojko J,Levin AAdoi
10.1177/019262339902700117subject
Has Abstractpub_date
1999-01-01 00:00:00pages
95-100issue
1eissn
0192-6233issn
1533-1601journal_volume
27pub_type
杂志文章,评审abstract::Our previous studies showed that protein kinase Cepsilon (PKCepsilon) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma forma...
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