Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats.
OBJECTIVE
The antineoplastic anthracycline doxorubicin can induce a dose-dependent cardiomyopathy that limits the total cumulative dose prescribed to cancer patients. In both preclinical and clinical studies, pretreatment with dexrazoxane, an intracellular iron chelator, partially protects against anthracycline-induced cardiomyopathy. To identify potential additional cardioprotective treatment strategies, we investigated early doxorubicin-induced changes in cardiac gene expression.


METHODS
Spontaneously hypertensive male rats (n = 47) received weekly intravenous injections of doxorubicin (3 mg/kg) or saline 30 min after pretreatment with dexrazoxane (50 mg/kg) or saline by intraperitoneal injection. Cardiac samples were analyzed 24 h after the first (n = 20), second (n = 13), or third (n = 14) intravenous injection on days 1, 8, or 15 of the study, respectively.


RESULTS
Rats receiving three doses of doxorubicin had minimal myocardial alterations that were attenuated by dexrazoxane. Cardiac expression levels of genes associated with the Nrf2-mediated stress response were increased after a single dose of doxorubicin, but not affected by cardioprotectant pretreatment. In contrast, an early repressive effect of doxorubicin on transcript levels of genes associated with mitochondrial function was attenuated by dexrazoxane pretreatment. Dexrazoxane had little effect on gene expression by itself.


CONCLUSIONS
Genomic analysis provided further evidence that mitochondria are the primary target of doxorubicin-induced oxidative damage that leads to cardiomyopathy and the primary site of cardioprotective action by dexrazoxane. Additional strategies that prevent the formation of oxygen radicals by doxorubicin in mitochondria may provide increased cardioprotection.
Thompson
Karol L
KL
Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. karol.thompson@fda.hhs.gov
Rosenzweig
Barry A
BA
Zhang
Jun
J
Knapton
Alan D
AD
Honchel
Ronald
R
Lipshultz
Steven E
SE
Retief
Jacques
J
Sistare
Frank D
FD
Herman
Eugene H
EH
D000818:Animals; D008297:Male; D051381:Rats; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020107:Troponin T / Q000097:blood / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D011929:Razoxane; D020107:Troponin T; D051267:NF-E2-Related Factor 2