Prevention of chronic anthracycline cardiotoxicity in the adult Fischer 344 rat by dexrazoxane and effects on iron metabolism.
OBJECTIVE
Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1-IRE binding, may be an important mechanism of anthracycline cardiotoxicity.


METHODS
This study examined the role of IRP1-IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5-6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1-IRE binding.


RESULTS
Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin.


CONCLUSIONS
IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.
Research Service, VA Medical Center (111), 500 W Fort St, Boise, ID, 83702, USA. barry.cusack@med.va.gov
B J
BJ
Cusack
H
H
Gambliel
B
B
Musser
N
N
Hadjokas
S E
SE
Shadle
H
H
Charlier
R D
RD
Olson
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002614:Chelating Agents / Q000627:therapeutic use*; D003630:Daunorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011929:Razoxane / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D002614:Chelating Agents; D035925:Iron-Regulatory Proteins; D011929:Razoxane; D035941:Iron Regulatory Protein 1; D003630:Daunorubicin