CHANGES OF TOXICOLOGICAL CHARACTERISTICS OF ADRIAMYCIN BY CONJUGATION WITH MACROMOLECULE

Toxicity of adriamycin-oxidized dextran (ADM-OXD), a newly developed antineoplastic macromolecule, was compared with that of adriamycin (ADM). ADM-OXD (0.7, 2.0mgADM/kg) and ADM (0.7mg/kg) were administered intravenously to male and female Wistar rats daily for 28 days. Upon observation of morphological changes at the same dose level (0.7mg/kg), toxic effects on the heart, kidney, hematopoietic-lymphatic system (lymph nodes, thymus, bone marrow, spleen), digestive tract (stomach) were found to be more pronounced in the ADM groups. Furthermore, hematological changes such as decrease in erythrocyte count and leucocyte count, were more significant in the ADM groups than in the ADM-OXD groups. On the other hand, the effect on the liver was specific to ADM-OXD, especially in the high dose groups. Not only hepatic dysfunction such as elevation of transaminase activities, but also morphological changes such as single cell necrosis, hyaline degeneration, and congestion, were found in these groups. To confirm these hepatotoxicities of ADM-OXD, ADM was monitored daily up to day 4. Here too, hepatotoxicity was specific to ADM-OXD. Since increase in TBA-reactive substances in the liver homogenate was found in close proportion to the induction of hepatic dysfunction, it was suggested that lipid peroxidation was one of the factors which caused hepatotoxicity.