Prevention by dexrazoxane of down-regulation of ryanodine receptor gene expression in anthracycline cardiomyopathy in the rat.
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.
Burke
B E
BE
Research Service, Department of Veterans Affairs Medical Center, Boise, Idaho, ID 83702, USA.
Gambliel
H
H
Olson
R D
RD
Bauer
F K
FK
Cusack
B J
BJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism; D003630:Daunorubicin / Q000633:toxicity*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D011929:Razoxane / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D011929:Razoxane; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D003630:Daunorubicin