COMPARISON OF THE TOXICITY PROFILES OF ISIS-1082 AND ISIS-2105, PHOSPHOROTHIOATE OLIGONUCLEOTIDES, FOLLOWING SUBACUTE INTRADERMAL ADMINISTRATION IN SPRAGUE-DAWLEY RATS

The systemic toxicity of two phosphorothioate oligonucleotides specifi c for herpes simplex viruses (ISIS 1082) and human papiloma virus (ISI S 2105) were evaluated following repeated intradermal injections of ve hicle control, 0.33, 2.17, or 21.7 mg/kg daily to Sprague-Dawley rats (10/sex/group) for 14 days. Animals were sacrificed 1 day after the la st dose, except for a portion of the ISIS 1082-treated animals (5/sex/ group) which were maintained for an additional 14-day recovery period. The profile of alterations noted for both compounds was very similar. Other than local signs of irritation at the site of injection, there were no clinical signs of toxicity or treatment-related mortality, but there was a slight decrease in body weight gain for the 21.7 mg/kg do se groups. Alterations in hematology parameters included dose-dependen t thrombocytopenia and anemia. Alterations in serum chemistry paramete rs were suggestive of mild alterations in hepatic metabolism, with inc reases in liver transaminases and bilirubin, along with decreases in a lbumin and cholesterol. Both spleen and liver weights were significant ly elevated in a dose-dependent fashion. Histopathological alterations noted in liver, kidney, lung, injection site skin, and spleen were ch aracterized as perivascular and interstitial infiltrates of macrophage s and monocytes. Additional microscopic alterations in the spleen incl uded mild lymphoid hyperplasia (seen in lymph nodes as well), and extr amedullary hematopoiesis. Treatment-related cytopenias were likely rel ated to mild, focal hypocellularity in the bone marrow. Alterations in ISIS 1082-treated animals were only partially reversed following the 14-day treatment-free period. In conclusion, repeated intradermal admi nistration of ISIS 1082 and ISIS 2105 produced a similar spectrum of t oxicities, with liver, kidney, spleen, and bone marrow being identifie d as target tissues. Copyright (C) 1997 Elsevier Science Ireland Ltd.