Prevention by dexrazoxane of down-regulation of ryanodine receptor gene expression in anthracycline cardiomyopathy in the rat

Br J Pharmacol. 2000 Sep;131(1):1-4. doi: 10.1038/sj.bjp.0703538.


Anthracyclines can cause cumulative dose-related cardiotoxicity characterized by changes in Ca(2+) metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca(2+)-handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of dexrazoxane (ICRF-187), an iron chelator which prevents anthracycline cardiotoxicity, on RyR2 gene expression in rats treated chronically with daunorubicin. Daunorubicin (2.5 mg kg(-1) i.v. weekly for 6 weeks) produced cardiotoxicity as demonstrated by histopathologic changes. The ryanodine receptor/glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA ratio was decreased by 38+/-3% (P<0.02) compared to values in control rats. Dexrazoxane pre-treatment (50 mg kg(-1); 1 h prior to each daunorubicin injection) prevented the decrease in RyR2/GAPDH mRNA ratio and histopathologic lesions in daunorubicin-treated rats. This is the first report that a protective agent such as dexrazoxane can ameliorate the decreased expression of a specific gene involved in anthracycline-induced cardiotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity*
  • Cardiomyopathies / chemically induced*
  • Cardiomyopathies / metabolism
  • Daunorubicin / toxicity*
  • Down-Regulation
  • Gene Expression Regulation / drug effects*
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Male
  • RNA, Messenger / analysis
  • Rats
  • Rats, Inbred F344
  • Razoxane / pharmacology*
  • Ryanodine Receptor Calcium Release Channel / genetics*


  • Antibiotics, Antineoplastic
  • RNA, Messenger
  • Ryanodine Receptor Calcium Release Channel
  • Razoxane
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Daunorubicin