Modification of cyclophosphamide-induced pulmonary toxicity in normal mice.

The effects of fractionated doses, in vivo thiol modulation, and antifibrinolytic therapy on the expression of lung damage induced by cyclophosphamide (Cy) were evaluated in C3H mice. The protein content of lung lavage samples taken 4 days after Cy treatment was used as an early indicator of damage. In fractionation studies, little difference in lung protein was observed when 200 mg of Cy/kg was administered as a single dose or as two or four equal doses given daily, suggesting that little sparing effect occurred with fractionated doses of Cy. In experiments that tested the effects of exogenous thiol administration, mice treated with WR-2721 before Cy were protected against lung damage, whereas the use of sodium thiosulfate or mesna did not give this protection. Treatment with epsilon-aminocaproic acid, which inhibits the breakdown of fibrin clots, did not result in enhanced Cy damage as measured by lung lavage or breathing rate; this suggests that the extended presence of fibrin per se did not contribute to Cy-induced pulmonary damage.