Abstract
Anticancer therapy with doxorubicin (DOX) and other quinone anthracyclines is limited by severe cardiotoxicity, reportedly because semiquinone metabolites delocalize Fe(II) from ferritin and generate hydrogen peroxide, thereby promoting hydroxyl radical formation and lipid peroxidation. Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results. To investigate the role and mechanism(s) of cardiac lipid peroxidation in a clinical setting, we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine cancer patients undergoing intravenous treatments with DOX. Before treatment, CD were unexpectedly higher in coronary sinus than in femoral artery (342±131 vs 112±44 nmol/ml, mean±SD; P <0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation. This was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer. The infusion of a standard dose of 60 mg DOX/m2 rapidly (~ 5 min) abolished the difference in CD levels between coronary sinus and femoral artery (134±95 vs 112±37 nmol/ml); moreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by ~ 80% in response to the infusion of as little as 13 mg DOX/m2. Thus, DOX appeared to inhibit cardiac lipid peroxidation in a rather potent manner. Corollary in vitro experiments were performed using myocardial biopsies from patients undergoing aortocoronary bypass grafting. These experiments suggested that the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequately by cardiac isoferritins and became redox inactive when hydrogen peroxide was included to simulate DOX metabolism and hydroxyl radical formation. Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in DOX-treated patients. Other processes might therefore contribute to the cardiotoxicity of DOX.
| Original language | English |
|---|---|
| Pages (from-to) | 650-661 |
| Number of pages | 12 |
| Journal | Journal of Clinical Investigation |
| Volume | 98 |
| Issue number | 3 |
| Publication status | Published - Aug 1 1996 |
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Keywords
- cardiotoxicity
- doxorubicin
- free radicals
- iron
- lipid peroxidation
ASJC Scopus subject areas
- Medicine(all)
Cite this
Paradoxical inhibition of cardiac lipid peroxidation in cancer patients treated with doxorubicin : Pharmacologic and molecular reappraisal of anthracycline cardiotoxicity. / Minotti, Giorgio; Mancuso, Cesare; Frustaci, Andrea; Mordente, Alvaro; Santini, Stefano A.; Calafiore, Antonio Maria; Liberi, Giovanni; Gentiloni, Nicolo'.
In: Journal of Clinical Investigation, Vol. 98, No. 3, 01.08.1996, p. 650-661.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Paradoxical inhibition of cardiac lipid peroxidation in cancer patients treated with doxorubicin
T2 - Pharmacologic and molecular reappraisal of anthracycline cardiotoxicity
AU - Minotti, Giorgio
AU - Mancuso, Cesare
AU - Frustaci, Andrea
AU - Mordente, Alvaro
AU - Santini, Stefano A.
AU - Calafiore, Antonio Maria
AU - Liberi, Giovanni
AU - Gentiloni, Nicolo'
PY - 1996/8/1
Y1 - 1996/8/1
N2 - Anticancer therapy with doxorubicin (DOX) and other quinone anthracyclines is limited by severe cardiotoxicity, reportedly because semiquinone metabolites delocalize Fe(II) from ferritin and generate hydrogen peroxide, thereby promoting hydroxyl radical formation and lipid peroxidation. Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results. To investigate the role and mechanism(s) of cardiac lipid peroxidation in a clinical setting, we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine cancer patients undergoing intravenous treatments with DOX. Before treatment, CD were unexpectedly higher in coronary sinus than in femoral artery (342±131 vs 112±44 nmol/ml, mean±SD; P <0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation. This was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer. The infusion of a standard dose of 60 mg DOX/m2 rapidly (~ 5 min) abolished the difference in CD levels between coronary sinus and femoral artery (134±95 vs 112±37 nmol/ml); moreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by ~ 80% in response to the infusion of as little as 13 mg DOX/m2. Thus, DOX appeared to inhibit cardiac lipid peroxidation in a rather potent manner. Corollary in vitro experiments were performed using myocardial biopsies from patients undergoing aortocoronary bypass grafting. These experiments suggested that the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequately by cardiac isoferritins and became redox inactive when hydrogen peroxide was included to simulate DOX metabolism and hydroxyl radical formation. Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in DOX-treated patients. Other processes might therefore contribute to the cardiotoxicity of DOX.
AB - Anticancer therapy with doxorubicin (DOX) and other quinone anthracyclines is limited by severe cardiotoxicity, reportedly because semiquinone metabolites delocalize Fe(II) from ferritin and generate hydrogen peroxide, thereby promoting hydroxyl radical formation and lipid peroxidation. Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results. To investigate the role and mechanism(s) of cardiac lipid peroxidation in a clinical setting, we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine cancer patients undergoing intravenous treatments with DOX. Before treatment, CD were unexpectedly higher in coronary sinus than in femoral artery (342±131 vs 112±44 nmol/ml, mean±SD; P <0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation. This was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer. The infusion of a standard dose of 60 mg DOX/m2 rapidly (~ 5 min) abolished the difference in CD levels between coronary sinus and femoral artery (134±95 vs 112±37 nmol/ml); moreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by ~ 80% in response to the infusion of as little as 13 mg DOX/m2. Thus, DOX appeared to inhibit cardiac lipid peroxidation in a rather potent manner. Corollary in vitro experiments were performed using myocardial biopsies from patients undergoing aortocoronary bypass grafting. These experiments suggested that the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequately by cardiac isoferritins and became redox inactive when hydrogen peroxide was included to simulate DOX metabolism and hydroxyl radical formation. Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in DOX-treated patients. Other processes might therefore contribute to the cardiotoxicity of DOX.
KW - cardiotoxicity
KW - doxorubicin
KW - free radicals
KW - iron
KW - lipid peroxidation
UR - http://www.scopus.com/inward/record.url?scp=0029910238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029910238&partnerID=8YFLogxK
M3 - Article
C2 - 8698856
AN - SCOPUS:0029910238
VL - 98
SP - 650
EP - 661
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
ER -