|Abstract or Summary
- Investigations were undertaken to characterize the toxicity in
animals treated with 1, 3-Bis(2-chloroethyl)-1-nitrosourea (BCNU).
Primary experimental interest in this compound had centered around
its antineoplastic activity; however, clinical application of the compound
resulted in the appearance of delayed toxicity symptoms. A
critical evaluation of the toxicity associated with BCNU has not been
reported, therefore, these studies were undertaken to fill this need.
That BCNU produced a latent toxicity was verified in acute
lethality studies. No deaths occurred prior to five days post treatment
even with doses three to five times the median lethal dose
(LD50). The LD50, determined by the administration of graded,
single oral doses of BCNU to rats, was found to be 30 mg/kg when
the observation time was 30 days. If the cut-off time was extended
to 70 days, 30 mg/kg resulted in mortality of all treated animals. Furthermore, if the cut-off time was set at 90-100 days, a single dose
of 20 mg/kg killed all treated animals. Similar mortality patterns
were observed for another nitrosourea derivative, 1-(2-chloroethyl)
-3-cyclohexyl-l-nitrosourea (CCNU), but this congener was only half
as potent as BCNU on either a weight or molar basis.
Decreased body weight of the BCNU treated animals was one of
the most conspicuous features of the toxicity. The magnitude of this
effect was dose related and could be attributed to alterations in several
metabolic systems. Parallel reductions of plasma volume and
body weight suggested that the decreased animal weight reflected loss
of body water. Decreased food consumption also contributed to weight
losses. In addition, increased blood urea nitrogen levels and diminished
weights of liver, kidney and brain suggested that an increase
of catabolism may have complemented the body weight losses.
A prolonged and progressive bimodal hepatotoxicity was revealed
by a series of standard hepatic function techniques following
BCNU administration to rats. By one week post treatment, all doses
of BCNU resulted in prolonged pentobarbital hypnosis and enhanced
bromsulfalein (BSP) retention. Enzyme induction with phenobarbital
significantly decreased the prolongation of narcosis. Elevations of
serum bilirubin (SBr) appeared later, being delayed by as much as
63 days at the lowest dose. SBr was direct-reacting at early stages
but later shifted to indirect reacting coincidental with a reduction of BSP retention. Histopathological evaluation revealed early pericholangitis
and necrosis of bile ductules. This pattern progressed
to one of focal necrosis of the hepatocytes, biliary cirrhosis and
proliferation of biliary epithelium.
Hematological examination disclosed an early leukopenia with
a later decrease in hematocrit and erythrocyte levels. Hemoglobin
levels, mean corpuscular hemoglobin, mean corpuscular hemoglobin
concentration, as well as mean corpuscular volume did not
deviate statistically from control levels. A diminished albumin-globulin
ratio was also detected. Plasma volume and total blood
volume were severely decreased at extended times. When expressed
as per cent of body weight however, both plasma and blood volume
did not deviate from control values. This was consistent with the
hypothesis that the lower body weights of treated animals reflected
losses of total body water.
High doses of BCNU were also found to decrease intestinal and
blood levels of serotonin. Brain levels of serotonin were significantly
elevated. These actions of BCNU may make the drug especially useful
as an investigative tool for evaluating the biological importance
of serotonin. In addition, some of the signs of BCNU toxicity may
be explained by the serotonin alterations.
The ability of BCNU to produce a severe and delayed toxicity
with a wide diversity of effects was verified in these studies. The pattern of mortality induced by BCNU administration appeared to
result from a multiplicity of factors rather than a single toxic manifestation.
The mechanism(s) by which the physiological systems
were compromised must await further investigations.