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.