Anthracycline cardiotoxicity: in vivo and in vitro effects on biochemical parameters and heart ultrastructure of the rat.
The premise of this study is that mitochondrial lesions caused by anthracyclines lead directly to cardiotoxicity. We compared several biochemical parameters, including endogenous cellular respiration, adenosine and guanosine triphosphate levels, and 14C-amino acid incorporation, of rat hearts treated with doxorubicin and some of its derivatives, recent products of pharmacological research aimed at selecting less toxic antiblastic agents. In rats treated in vivo, we further examined the ultrastructural changes induced by anthracycline antibiotics in order to elucidate which biochemical parameters were consistent with the morphological lesions. Our data indicate that mitochondria are the target of the anthracycline effects and that oxygen uptake and nucleotide levels may be regarded as markers of the toxicity when evaluating new drugs before their clinical use. The lack of cytoplasmatic or endoplasmatic reticulum alterations may account for the failure of anthracyclines to affect amino acid incorporation. In any event, the rate of protein synthesis cannot serve as a marker of cardiac toxicity. In this context, epidoxorubicin and iododoxorubicin are two derivatives characterized by less cardiotoxic potential than doxorubicin and thus appear to be promising antiblastic agents.
Cini Neri
G
G
Institute of General Pathology, University of Florence, Italy.
Neri
B
B
Bandinelli
M
M
Del Tacca
M
M
Danesi
R
R
Riccardi
R
R
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007930:Leucine / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects*; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains
D000903:Antibiotics, Antineoplastic; D006153:Guanosine Diphosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D007930:Leucine