Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187).

Adult beagle dogs were given doxorubicin (1.0 mg/kg body weight i.v.) either alone or 30 min after ICRF-187 (NSC 169780) (12.5 mg/kg body weight i.p.) at weekly intervals. Control dogs received 0.9% NaCl solution i.v. 30 min after ICRF-187 i.p. (12.5 mg/kg body weight). One week after the 15th injection (300 mg/sq m total dose), the animals were sacrificed. The frequency and extent of cellular lesions were graded on a scale of 0 to 4+. Such lesions, consisting mainly of vacuolization and myofibrillar loss, were noted in the hearts of all six dogs given doxorubicin alone. The lesions were severe (4+) in five of these animals and moderate (2+) in one. In contrast, no abnormalities were noted in the hearts of four of the six dogs pretreated with ICRF-187 before doxorubicin administration; the remaining two animals in this group had minimal alterations (1+). At the dosage regimen used in the present experiments, doxorubicin did not induce lesions in lungs, liver, kidney, diaphragm, small intestine, or skeletal muscles. Comparable decreases in white blood cell count, red blood cell count, hemoglobin, and serum iron concentration were found in animals receiving doxorubicin with or without ICRF-187. Concurrent administration of ICRF-187 offers a promising means of reducing the chronic cardiotoxicity induced by doxorubicin.