Anthraquinone-induced cell injury: acute toxicity of carminomycin, epirubicin, idarubicin and mitoxantrone in isolated cardiomyocytes.
Acute toxic effects of the antineoplastic anthraquinones carminomycin, epirubicin, idarubicin and mitoxantrone were studied in primary cultures of cardiomyocytes, which were isolated from adult rats. Both time- and concentration-dependent changes of cell structure and viability (trypan blue exclusion) following incubation of myocytes with subclinical, clinical and toxic concentrations of the anthraquinones were examined by light microscopy. The area under the decay curve of viable and rod-shaped myocytes was used to express cytotoxicity of the drugs. Mitoxantrone was found to reduce cell viability and number of rod-shaped cells to the greatest extent, followed by carminomycin, idarubicin and epirubicin. A significantly lower accumulation in cardiomyocytes was obtained with epirubicin and idarubicin compared with carminomycin. An inhibitory effect on oxygen consumption by the cells occurred already at 0.1 microM with epirubicin, whereas inhibition caused by other anthraquinones was less pronounced. Our data indicate a weak association of net accumulation and the toxicity parameter IC50 for carminomycin and idarubicin. In contrast to these results, a more significant correlation of cytotoxicity and anthraquinone lipophilicity was found, which suggests that the lipophilic character of a particular anthraquinone may be an important factor in drug-induced acute cardiotoxicity.
Andersson
B S
BS
Institute of Oncology-Pathology, Department of Forensic Medicine, Karolinska Institutet, Stockholm, Sweden.
Eksborg
S
S
Vidal
R F
RF
Sundberg
M
M
Carlberg
M
M
D000818:Animals; D000880:Anthraquinones / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002360:Carubicin / Q000633:toxicity; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015251:Epirubicin / Q000633:toxicity; D015255:Idarubicin / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008297:Male; D008942:Mitoxantrone / Q000633:toxicity; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000880:Anthraquinones; D000970:Antineoplastic Agents; D015251:Epirubicin; D008942:Mitoxantrone; D002360:Carubicin; D015255:Idarubicin