Effects of bis-chloronitrosourea (BCNU) on pulmonary and serum angiotensin converting enzyme activity in rats

The anticancer drug bis-chloronitrosourea (BCNU) causes potentially life-threatening lung injury in a high percentage of patients. Because changes in the activities of pulmonary and serum angiotensin converting enzyme (ACE) have been reported previously to reflect toxic pulmonary damage by certain agents, we have investigated the effects of BCNU on pulmonary and serum ACE of rats. In vitro, BCNU had a direct inhibitory effect on both serum ACE and pulmonary ACE. In vivo, a large single dose of BCNU (80 mg/kg, i.p.) did not alter pulmonary ACE nor cause histologically observable acute lung damage. However, serum ACE dropped by 25% within 1 hr after drug. A multi-dose regimen, consisting of 5 mg BCNU/kg once per week for 6 weeks, caused marked pulmonary injury, which continued to develop in severity over several weeks following the completion of dosing. Lung ACE after four doses (total of 20 mg BCNU/kg) was depressed by 40% and remained low until dosing was completed. Following the final dose, lung ACE returned to control within 2 weeks. However, after an additional 2 weeks both lung and serum ACE had decreased by 35 and 25% respectively. It appears that ACE may provide a useful biochemical monitor for BCNU-induced pulmonary toxicity, but careful attention must be given to the time-course of changes in the enzyme activity.