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Citations to this article

Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine.
J H Doroshow, … , I Ifrim, C E Myers
J H Doroshow, … , I Ifrim, C E Myers
Published October 1, 1981
Citation Information: J Clin Invest. 1981;68(4):1053-1064. https://doi.org/10.1172/JCI110328.
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Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine.

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Abstract

This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.

Authors

J H Doroshow, G Y Locker, I Ifrim, C E Myers

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Prevention of doxorubicin-induced cardiomyopathy by reduced glutathione
F Villani, M Galimberti, F Zunino, E Monti, A Rozza, E Lanza, L Favalli, P Poggi
Cancer Chemotherapy and Pharmacology 1991
New Drugs, Concepts and Results in Cancer Chemotherapy
FM Muggia
1991
Effect of Glutathione and N-Acetylcysteine on in Vitro and in VIVO Cardiac Toxicity of Doxorubicin
F Villani, M Galimberti, E Monti, F Piccinini, E Lanza, A Rozza, L Favalli, P Poggi, F Zunino
Free Radical Research 1990
Doxorubicin (adriamycin): A critical review of free radical-dependent mechanisms of cytotoxicity
HG Keizer, HM Pinedo, GJ Schuurhuis, H Joenje
Pharmacology & Therapeutics 1990
Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump
H Harada, BJ Cusack, RD Olson, W Stroo, J Azuma, T Hamaguchi, SW Schaffer
Biochemical Pharmacology 1990
Effects of three cysteine pro-drugs on bleomycin-induced lung fibrosis in hamsters
DM Hyde, MJ Schiedt, GA Krishna, SN Giri
Pathology 1990
Antioxidants in Therapy and Preventive Medicine
I Emerit, L Packer, C Auclair
1990
Free radical formation by antitumor quinones
G Powis
Free radical biology & medicine 1989
Increasing therapeutic effect and reducing toxicity of doxorubicin by N-acyl dehydroalanines
P Buc-Calderon, M Praet, JM Ruysschaert, M Roberfroid
European Journal of Cancer and Clinical Oncology 1989
Effect of diethyldithiocarbamate on toxicity of doxorubicin, cyclophosphamide and cis-diamminedichloroplatinum (II) on mice haemopoietic progenitor cells
IM Pannacciulli, RA Lerza, GV Bogliolo, MP Mencoboni, AG Saviane
British Journal of Cancer 1989
Reduction of doxorubicin toxicity by methylene blue in cultured rat myocardial cells
RJ Anderson, JR Babson
Biochemical Pharmacology 1989
Current Therapy in Nephrology
VE Andreucci, AD Canton
1989
Evidence for the lack of involvement of free radicals in adriamycin-induced histamine release from rat peritoneal cells
L Candussio, FB Klugmann, G Decorti, L Baldini
Agents and Actions 1988
Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: Possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation
SR Powell, PB McCay
Toxicology and Applied Pharmacology 1988
DEACTIVATION OF SINGLET MOLECULAR OXYGEN BY THIOLS AND RELATED COMPOUNDS, POSSIBLE PROTECTORS AGAINST SKIN PHOTOSENSITIVITY
M Rougee, RV Bensasson, EJ Land, R Pariente
Photochemistry and Photobiology 1988
Mitochondrial sulfhydryl group modification by adriamycin aglycones
PM Sokolove
FEBS Letters 1988
A new class of free radical scavengers reducing adriamycin mitochondrial toxicity
M Praet, PB Calderon, G Pollakis, M Roberfroid, JM Ruysschaert
Biochemical Pharmacology 1988
Na+-independent release of Ca2+ from rat heart mitochondria
PM Sokolove, RG Shinaberry
Biochemical Pharmacology 1988
Perspectives in Basic and Applied Toxicology
B Ballantyne
Perspectives in Basic and Applied Toxicology 1988
Protective Effect of the Bispiperazinedione ICRF-187 against Doxorubicin-Induced Cardiac Toxicity in Women with Advanced Breast Cancer
JL Speyer, MD Green, E Kramer, M Rey, J Sanger, C Ward, N Dubin, V Ferrans, P Stecy, A Zeleniuch-Jacquotte, J Wernz, F Feit, W Slater, R Blum, F Muggia
New England Journal of Medicine 1988
Oxygen Radicals in the Pathophysiology of Heart Disease
PK Singal
1988
Mechanism of anthraquinone-induced calcium release from skeletal muscle sarcoplasmic reticulum
JJ Abramson, E Buck, G Salama, JE Casida, IN Pessah
The Journal of biological chemistry 1988
Decreased ATPase activity in adriamycin nephrosis is independent of proteinuria
WW Bakker, D Kalicharan, J Donga, CE Hulstaert, MJ Hardonk
Kidney International 1987
Amelioration of chronic anthracycline cardiotoxicity by ICRF-187 and other compounds
EH Herman, VJ Ferrans
Cancer Treatment Reviews 1987
Metabolism and reactions of quinoid anticancer agents
G Powis
Pharmacology & Therapeutics 1987
Failure of systemic N-acetyl cysteine to protect the rat lung against bleomycin toxicity
HE Ward, A Nicholson, N Berend
Pathology 1987
Organ Directed Toxicities of Anticancer Drugs
MP Hacker, JS Lazo, TR Tritton
1987
New approaches to the possible prevention of side effects of chemotherapy by nutrition
J Pinto, GB Raiczyk, YP Huang, RS Rivlin
Cancer 1986
Mitigation of an anthracycline-induced cardiomyopathy by pretreatment with razoxane: a quantitative morphological assessment
VW Fischer, GM Wang, NH Hobart
Virchows Archiv B Cell Pathology Including Molecular Pathology 1986
Inhibitors of adriamycin-induced histamine release in vitro limit adriamycin cardiotoxicity in vivo
FB Klugmann, G Decorti, L Candussio, V Grill, F Mallardi, L Baldini
British Journal of Cancer 1986
Lack of effect of glutathione depletion on cytotoxicity, mutagenicity and DNA damage produced by doxorubicin in cultured cells
G Capranico, N Babudri, G Casciarri, L Dolzani, RA Gambetta, E Longoni, B Pani, C Soranzo, F Zunino
Chemico-Biological Interactions 1986
Prevention of Adriamycin Cardiotoxicity by Niacin, Isocitrate or N-acetyl-cysteine in Mice
A Schmitt-Gräff, ME Scheulen
Pathology - Research and Practice 1986
Failure of N-acetylcysteine to protect against cis-dichlorodiammine-platinum(II)-induced hematopoietic toxicity in mice
R Lerza, G Bogliolo, C Muzzulini, I Pannacciulli
Life Sciences 1986
Role of reactive oxygen intermediates in the hepatotoxicity of endotoxin
P Ghezzi, B Saccardo, B Marina
Immunopharmacology 1986
Doxorubicin cardiac toxicity manifesting seven years after treatment. Case report and review
CE Freter, TC Lee, ME Billingham, L Chak, MR Bristow
The American Journal of Medicine 1986
A possible role for membrane lipid peroxidation in anthracycline nephrotoxicity
EG Mimnaugh, MA Trush, TE Gram
Biochemical Pharmacology 1986
Doxorubicin (adriamycin)-induced cardiotoxicity in turkey poults: An animal model
CM Czarnecki
Comparative Biochemistry and Physiology Part C: Comparative Pharmacology 1986
The oxygen free radical system: A fundamental mechanism in the production of myocardial necrosis
JA Thompson, ML Hess
Progress in Cardiovascular Diseases 1986
Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques
E Jucker
1986
Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical
JH Doroshow, KJ Davies
The Journal of biological chemistry 1986
CARCINOGENICITY OF SOME ANTICANCER DRUGS—A SURVEY
EJ Lien, X Ou
Journal of Clinical Pharmacy and Therapeutics 1985
Oxygen radicals in biological processes (survey)
IB Afanas'ev
Pharmaceutical Chemistry Journal 1985
MODIFYING INTRACELLULAR REDOX BALANCE: AN APPROACH TO IMPROVING THERAPEUTIC INDEX
WJ Hrushesky, P Wood, R Olshefski, S Meshnick, JW Eaton
The Lancet 1985
Ultrastructural features of Adriamycin-induced skeletal and cardiac muscle toxicity
JH Doroshow, C Tallent, JE Schechter
The American Journal of Pathology 1985
Effect of doxorubicin-enhanced hydrogen peroxide and hydroxyl radical formation on calcium sequestration by cardiac sarcoplasmic reticulum
RN Harris, JH Doroshow
Biochemical and Biophysical Research Communications 1985
The effect of N-acetylcysteine on toxicity of cyclophosphamide and doxorubicin on murine hemopoietic progenitors
G Massa, C Muzzulini, G Bogliolo, I Pannacciulli
Life Sciences 1985
Usefulness of a free radical scavenger in preventing doxorubicin-induced heart failure in dogs
DV Unverferth, CV Leier, SP Balcerzak, RL Hamlin
The American Journal of Cardiology 1985
Free radical production from normal and adriamycin-treated rat cardiac sarcosomes
PJ Thornalley, NJ Dodd
Biochemical Pharmacology 1985
Studies on the mechanism of action of quinone antitumor agents
A Begleiter
Biochemical Pharmacology 1985
Progress in Medicinal Chemistry
JR Brown, SH Imam
Progress in Medicinal Chemistry 1985
Oxidative Stress
A Stern
Oxidative Stress 1985
Inhibition of bleomycin lung toxicity by N-acetyl cysteine in the rat
N Berend
Pathology 1985
Recent Advances in Biological Membrane Studies
L Packer
1985
Evaluation of free radical effects and catecholamine alterations in adriamycin cardiotoxicity
JA Jackson, JP Reeves, KH Muntz, D Kruk, RA Prough, JT Willerson, LM Buja
The American Journal of Pathology 1984
Prevention of adriamycin (ADR)-induced cardiotoxicity in rats using methylprednisolone (MP)
KS Dasmahapatra, M Vezeridis, U Rao, R Perez-Brett, CP Karakousis
Journal of Surgical Research 1984
Animal models of drug-induced cardiomyopathy
CM Czarnecki
Comparative Biochemistry and Physiology Part C: Comparative Pharmacology 1984
Nutritional and Toxicological Aspects of Food Safety
M Friedman
1984
Platinum Coordination Complexes in Cancer Chemotherapy
MP Hacker, EB Douple, IH Krakoff
1984
Indication of reduced doxorubicin-induced cardiac toxicity by additional treatment with antioxidative substances
R Lenzhofer, D Magometschnigg, R Dudczak, C Cerni, C Bolebruch, K Moser
Experientia 1983
Enhancement of adriamycin toxicity by carboxymethylcellulose in mice
G Decorti, FB Klugmann, F Mallardi, R Brovedani, G Baldini, L Baldini
Toxicology and Applied Pharmacology 1983
Destruction of Phosphilipids and Respiratory-Chain Activity in Pig=Heart Submitochondrial Particles Induced by an Adriamycin-Iron Complex
PK JENSEN
European Journal of Biochemistry 1983
Cardiotoxic effects of anthracyclines
MR Bristow
The Western journal of medicine 1983
Detection of antineoplastic agent induced cardiotoxicity by 31P NMR of perfused rat hearts
TC Ng, JP Daugherty, WT Evanochko, SB Digerness, JR Durant, JD Glickson
Biochemical and Biophysical Research Communications 1983
1,4-Bis{2-[(2-hydroxyethyl)amino]ethylamino}-9, 10-anthracenedione, an anthraquinone antitumour agent that does not cause lipid peroxidation in vivo; Comparison with daunorubicin
LH Patterson, BM Gandecha, JR Brown
Biochemical and Biophysical Research Communications 1983
Comparative cardiac oxygen radical metabolism by anthracycline antibiotics, mitoxantrone, bisantrene, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, and neocarzinostatin
JH Doroshow, KJ Davies
Biochemical Pharmacology 1983
Aktuelle Probleme der Hämatologie und internistischen Onkologie
CG Schmidt
1983
EFFECT OF TOCOPHEROL AND SELENIUM ON DEFENSES AGAINST REACTIVE OXYGEN SPECIES AND THEIR EFFECT ON RADIATION SENSITIVITY
CE Myers, A Katki, E Travis
Annals of the New York Academy of Sciences 1982
Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex
CE Myers, L Gianni, CB Simone, R Klecker, R Greene
Biochemistry 1982
Anthracycline Antibiotics in Cancer Therapy
FM Muggia, CW Young, SK Carter
1982

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