Studies on the toxicity of the carcinostatic compound 1, 3-bis (2-chloroethyl)-1-nitrosourea Public Deposited

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  • 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.
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