In vivo prevention of adriamycin cardiotoxicity by cyclosporin A or FK506.

The use of adriamycin, an antitumour agent, is restricted by its cardiotoxicity. The objective of this study was to investigate the role of mitochondrial Ca2+ in adriamycin-induced cardiotoxicity and the effect of either cyclosporin A (CsA) or tacrolimus (FK506) on that cardiotoxicity. A single dose of adriamycin (10 mg/kg body weight) caused myocardial damage that was manifested by elevation of serum enzymes, glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), lactate dehydrogenase isoenzyme (LDH-iso) and creatine phosphokinase isoenzyme (CPK2-MB). The permeability of heart inner mitochondrial membrane of adriamycin-treated rats was examined. Tetraphenyl phosphonium ion (TPP+) uptake, estimated with a TPP+-sensitive electrode was used to monitor changes in heart inner mitochondrial membrane potential. Ca2+ efflux was measured spectrophotometrically with the Ca2+ indicator arsenazo III. The ability of heart mitochondria isolated from adriamycin treated rats to retain accumulated Ca2+ or TPP+ was sharply reduced. The increase of diagnostic serum enzymes and isoenzymes and the reduced ability to retain Ca2+ or TPP+ by heart mitochondria were restored to almost the normal levels when (500 microg/kg body weight) of CsA or FK506 were injected with adriamycin. The data suggested that adriamycin cardiotoxicity might be due to the increase of inner membrane permeability in heart mitochondria as a result of increasing the sensitivity of a Ca2+ dependent-pore of the inner mitochondrial membrane to calcium, leading to dissipation of membrane potential and release of pre-accumulated Ca2+. Suitable antagonists of Ca2+-dependent pore formation such as CsA or FK506 may improve heart tolerance to adriamycin.