Characterization of experimental mitoxantrone cardiotoxicity and its partial inhibition by ICRF-187 in cultured neonatal rat heart cells.
Mitoxantrone cardiotoxicity was investigated in isolated neonatal rat heart myocytes treated for 3 h in the presence or absence of the metal chelator ICRF-187. Electron microscopy studies of mitoxantrone-treated myocytes showed disorganized myofibrillar structures, swollen mitochondria, and extensive vacuolization. Cardiotoxicity, reflected as the ratio of intracellular ATP/protein and the loss of spontaneous beating, was only partially reduced by continuous ICRF-187 concentrations up to 50 micrograms/ml. ICRF-187 induced myocyte protection which was dependent on the dose and duration of exposure. ICRF-187 also reduced the cardiotoxicity of doxorubicin to a lesser extent and reduced the toxicity of a postulated cyclic mitoxantrone metabolite. However, the cardiotoxicity of ametantrone, a nonmetal-binding analogue of mitoxantrone, was unaltered with ICRF-187. The antitumor activity of mitoxantrone was unaltered by ICRF-187 in human tumor cells and in P-388-bearing mice. In addition, ICRF-187 allowed for 50% greater cumulative dosing in normal mice that, nonetheless, showed extensive histological heart damage 7 wk after dosing. These studies show that ICRF-187 provides partial protection from mitoxantrone cardiotoxicity in vitro without impairing the drug's antitumor activity in vitro or in vivo. This facilitates greater cumulative drug dosing in normal mice. The postulated mechanism of cardioprotection is metal chelation, because ICRF-187 did not alter the toxicity of a nonchelating mitoxantrone analogue.
Shipp
N G
NG
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724.
Dorr
R T
RT
Alberts
D S
DS
Dawson
B V
BV
Hendrix
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D008942:Mitoxantrone / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity*; D009101:Multiple Myeloma / Q000188:drug therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011929:Razoxane; D000255:Adenosine Triphosphate; D008942:Mitoxantrone