Toxicity of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethylcellulose in mice.
Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon (IFN) inducer in rodents and, when suitably complexed with poly-L-lysine and carboxymethylcellulose [poly(I,C)-LC], also in primates and humans. In addition, poly(I,C)-LC has shown significant therapeutic activity in a number of preclinical tumor models and significant toxicity in both the preclinical and clinical settings. To better understand the toxicity of this agent, particularly in light of the previously reported bell-shaped dose response curve for immunomodulation and therapeutic activity, we undertook a pharmacological/toxicological study of poly(I,C)-LC. These experiments revealed that the injection of toxic doses of poly(I,C)-LC significantly reduced the body weight of animals and induced serological and histological abnormalities. We found that poly(I,C) is the toxic moiety of poly(I,C)-LC and that both agents induced pulmonary thrombosis as well as hepatic necrosis. The hepatic necrosis was reflected in serum enzyme levels, with significant increases in ornithine carbonyl transferase, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase levels. In addition, reduced platelet counts indicated a significant increase in platelet consumption in agreement with the thrombosis. There were, however, only minor changes in prothrombin and activated prothrombin times. It was of interest that coincubating poly(I,C)-LC and peritoneal macrophages in vitro resulted in the production of tumor necrosis factor, which has a similar pattern of toxicity; this finding suggests that poly(I,C)-LC's pattern of toxicity may be associated with the induction of TNF and/or IFN.
Hartmann
D
D
Preclinical Screening Laboratory, Frederick Cancer Research Facility, Md.
Schneider
M A
MA
Lenz
B F
BF
Talmadge
J E
JE
D000818:Animals; D002266:Carboxymethylcellulose Sodium; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010529:Peritoneal Cavity / Q000166:cytology / Q000187:drug effects; D011070:Poly I-C / Q000008:administration & dosage* / Q000633:toxicity; D011107:Polylysine / Q000008:administration & dosage*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D011107:Polylysine; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C