Toxic characteristics of the synthetic lipid A derivative DT-5461 in rats and monkeys.
We compared lethal toxicity and potential for splenomegaly and disseminated intravascular coagulation (DIC) of the lipid A derivative DT-5461 with those of compound 506 (C506) and bacterial lipopolysaccharide (LPS). These agents were given intravenously, by either bolus intravenous injection (2 ml/min) or drip infusion (3 ml/4 h), into the tail vein of rats under various regimens. In naive rats, the lethal dose after bolus intravenous injection was clearly higher than that after drip infusion for C506 and LPS, but not for DT-5461. In partially hepatectomized or D-galactosamine-treated rats, a marked enhancement of the lethality was observed for all agents relative to that in naive rats. Splenomegaly was commonly seen in all surviving rats after treatment, and histopathological examination revealed lymphoid hyperplasia in the B-cell area of the white pulp zone and lympho-reticular cell proliferation of the red pulp zone. When administered intravenously by drip infusion to rats pretreated with 0.4 M lactic acid, both C506 and LPS provoked DIC. This was manifested by a decrease in platelet counts, prolongation of activated partial thromboplastin time (APTT), and an increase in fibrin-fibrinogen degradation products (FDP), with hepatocellular necrosis and glomercular fibrin thrombus formation. In contrast, DT-5461 showed no such toxic events with the same protocol. In14-day intravenous toxicity studies of DT-5461, rats were more susceptible to hepatocellular necrosis and splenomegaly than squirrel monkeys. These results demonstrate that DT-5461 is a promising compound, with antitumor activity dissociated from its toxic potential.
Tokyo Research and Development Center, Daiichi Pharmaceutical Co., Ltd., Japan.
N
N
Sagara-Ishijima
K
K
Furuhama
D000818:Animals; D004187:Disaccharides / Q000008:administration & dosage / Q000633:toxicity*; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced*; D006965:Hyperplasia / Q000139:chemically induced; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D013045:Species Specificity; D013163:Splenomegaly / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
D004187:Disaccharides; D008050:Lipid A; D008070:Lipopolysaccharides; C077208:DT 5461