Inhibition of endogenous respiration in rat heart slices as a measure of mitoxantrone cardiac toxicity.

Abstract

Anthracycline antibiotics are among the more active agents currently available for the treatment of solid tumors. Their use is limited by the development of severe cardiomyopathy. This makes it necessary to subject new anticancer agents to laboratory and clinical tests in order to determine their capacity to damage cardiac cells. Mitoxantrone is an anthracenedione derivative with structural and functional similarities to doxorubicin. Comparative trials on rat suggest that mitoxantrone induced cardiac toxicity might be less marked than that caused by doxorubicin, while some clinical studies report a significant incidence of cardiac failure following mitoxantrone administration. The present study was undertaken to evaluate (in vitro) the effect of increasing concentrations of mitoxantrone on respiratory control, measuring oxygen uptake of rat heart slices in a Warburg manometric apparatus. Over a period of 60 min, cellular endogenous respiration was progressively inhibited by increasing mitoxantrone concentration (from 5 to 20 microM). The date show that the rate of oxygen uptake levels off with time at all concentrations except the lowest (5 microM) and with the control. Oxygen uptake values range from 2.87 to 1.41 microliter/mg dry weight and differ significantly as compared to controls (p less than 0.01). The values of oxygen uptake between 0 and 20 min show that a linear correlation is approached by all the date group and if we consider an exponential relation (i.e., log slope versus dose), the linear correlation coefficient is somewhat improved (r = -0.939). These results indicate that mitoxantrone, in a manner analogous to doxorubicin, inhibits cellular respiration and impairs the cardiac respiratory control. This impairment is probably one of the aspects of cellular damage leading to cardiac failure. Moreover, in a recent study we observed the same pathological lesions induced by doxorubicin in the heart of rats treated with mitoxantrone.