The Pathomorphology of Daunorubicin-injured and ICRF-159 (Razoxane)-protected Murine Myocardium: Progress Report

Abstract

This study was designed to establish the feasibility of the mouse as a model for the investigations of (1) the cardiac myopathy associated with daunorubicin (DNR) administration and (2) the mitigation of this disorder by pretreatment with razoxane (RZ). BDF1 mice were divided into three groups: 12 mice were injected at 6-weekly intervals with DNR; a second group of 12 mice received the same regimen but, in addition, were pretreated each time with RZ; a third group was injected with the carrier only. Ten/twelve mice injected with DNR died within the length of the experiment (6 weeks), while 9/12 of the pretreated animals survived that time span. Four of the DNR-exposed group were sacrificed prior to death to permit ultrastructural examination. All 9 surviving RZ-pretreated mice were processed for electron microscopy. Myocardial tissue was also examined light microscopically and histochemically. The ultrastructure of the DNR-treated myocardium showed a number of focally distributed abnormalities, including changes in nuclear topography, early alterations demarcated by lysosomal aggregations, and dilatations of the sarcoplasmic reticulum, and more severe lesions consisting of large, coalesced vacuolar spaces within the cardiomyocytic cytoplasm and extensive distortion of the myofibrillar architecture. The heart protected by RZ, in general, only showed either minimal or mild changes. In a few animals, the protection did not appear to be as effective as in the majority of the pretreated mice. However, extensive structural alterations were never seen in the RZ-protected myocardium. These results confirm our previous preliminary findings that a DNR-associated cardiomyopathy is inducible in mice and that pretreatment with RZ may mitigate the structural alterations in this disorder.