Myocardial toxicity of high-dose cyclophosphamide in rabbits treated with daunorubicin

The present study was performed to evaluate experimentally the possible cardiotoxicity of high doses of cyclophosphamide after pretreatment with anthracyclines, a regimen used prior to bone marrow transplantation. A total of 27 rabbits received daunorubicin at a dose of 2.25 mg/kg per week for 10 weeks. At 1 week after the last daunorubicin dose, 13 of these rabbits received cyclophosphamide at 100 mg/kg per day x2 (total dose, 200 mg/kg). All animals were killed after 1 additional week. Seven rabbits received cyclophosphamide at 100 mg/kg per day x2 and two animals were given 50 mg/kg per day x2 without additional treatment. In all, 18 untreated rabbits served as controls. At 3 h before the animals were killed, they received [99mTc]-pyrophosphate i.v. Myocardial isotope activity was determined using a detector, and cardiac specimens were examined with a gamma-camera. Cardiotoxic effects were evaluated by myocardial isotope accumulation and pathologic changes were determined by morphology and by light and electron microscopy. The pathologic evaluation showed more frequent and widespread acute myocyte necrosis in daunorubicin/cyclophosphamide-treated rabbits as compared with those treated with daunorubicin or cyclophosphamide only. Myocardial isotope accumulation in rabbits treated with daunorubicin/cyclophosphamide was significantly higher then that in animals treated with either drug alone (2 alpha less than or equal to 0.001). Rabbits receiving cyclophosphamide as a single agent showed minor myocyte lesions but did not differ from controls in terms of isotope accumulation. We conclude that high-dose cyclophosphamide treatment on a dose schedule similar to that used prior to bone marrow transplantation and given soon after long-term daunorubicin therapy is considerably cardiotoxic.