Chronic cardiotoxicity of doxorubicin (Adriamycin) in the rat: Morphologic and biochemical investigations

Abstract

A cardiotoxic response similar to that occurring with chronic doxorubicin (Adriamycin, ADR) administration in man and rabbits has been produced in the new Zealand Black (NZB) rat. ADR was given by the iv or ip route in groups of rats at 2 mg/kg/week for 10 weeks, 1 mg/kg/week for 10 weeks, and 1 mg/kg on Monday, Wednesday, and Friday (MWF) with a week of rest and then repeating to a total of 10 injections. Rats on the weekly ADR schedule developed gross (ascites, pleural effusion, cardiomegaly) and microscopic (focal myocytic degeneration, interstitial and myocytic vacuolization, loss and disorganization of sarcomeres) evidence of cardiotoxicity during the 150-day period of observation. A dosage of 2 mg/kg/week iv in rats produced high mortality (45%) and decreased mean body weight gains compared to controls. This dosage given sc resulted in significant elevations in serum creatine phosphokinase and lactic dehydrogenase. Preliminary evidence suggests that cardiotoxicity may be diminished by ADR administration on a MWF rest-repeat schedule. The sensitivity of this strain of rat to the cardiotoxic effects of ADR provides a model system in which to evaluate simultaneously the chemotherapeutic effects of ADR on an experimental osteosarcoma and new therapeutic measures to ameliorate cardiotoxicity.