Effect of Glutathione and N-Acetylcysteine on in Vitro and in VIVO Cardiac Toxicity of Doxorubicin

Villani, F; Galimberti, M.; Monti, Elena; Piccinini, F; Lanza, Enrica; Rozza, A.; Favalli, L.; Poggi, Paola; Zunino, Franco

doi:10.3109/10715769009109677

Cited by 30 publications

(12 citation statements)

References 16 publications

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“…Doxorubicin is known to decrease GSH content (106,125,158), a vital antioxidant in striated muscle. Infusion of glutathione prevented the cardiac contractile impairment caused by doxorubicin (256). Other antioxidants also protect cardiac muscle function in doxorubicin-induced cardiotoxicity.…”

Section: Cardiac Musclementioning

confidence: 97%

Chemotherapy-Induced Weakness and Fatigue in Skeletal Muscle: The Role of Oxidative Stress

Gilliam

Clair

2011

Antioxidants & Redox Signaling

270

221

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Significance: Fatigue is one of the most common symptoms of cancer and its treatment, manifested in the clinic through weakness and exercise intolerance. These side effects not only compromise patient's quality of life (QOL), but also diminish physical activity, resulting in limited treatment and increased morbidity. Recent Advances: Oxidative stress, mediated by cancer or chemotherapeutic agents, is an underlying mechanism of the drug-induced toxicity. Nontargeted tissues, such as striated muscle, are severely affected by oxidative stress during chemotherapy, leading to toxicity and dysfunction. Critical Issues: These findings highlight the importance of investigating clinically applicable interventions to alleviate the debilitating side effects. This article discusses the clinically available chemotherapy drugs that cause fatigue and oxidative stress in cancer patients, with an in-depth focus on the anthracycline doxorubicin. Doxorubicin, an effective anticancer drug, is a primary example of how chemotherapeutic agents disrupt striated muscle function through oxidative stress. Future Directions: Further research investigating antioxidants could provide relief for cancer patients from debilitating muscle weakness, leading to improved quality of life. Antioxid. Redox Signal. 15, 2543-2563.

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Section: Cardiac Musclementioning

confidence: 97%

Chemotherapy-Induced Weakness and Fatigue in Skeletal Muscle: The Role of Oxidative Stress

Gilliam

Clair

2011

Antioxidants & Redox Signaling

270

221

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“…Based on the free radical hypothesis of cardiac damage, scavengers of free radicals have been evaluated. Classic antioxidants such as vitamin E [71], ascorbic acid [72] and N-acetyl cysteine [73], although having displayed very encouraging preclinical results and in pathophysiologic rationale, have not demonstrated clear benefits in clinical trials. Newer studies involving coenzyme Q [74] and flavonoids [75] have shown beneficial effects although this was not conclusive.…”

Section: Cardioprotective Agentsmentioning

confidence: 99%

Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood

Iarussi¹,

Indolfi²,

Casale³

et al. 2001

CMC

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The prevention of anthracycline cardiotoxicity is particularly important in children who can be expected to survive for decades after cancer chemotherapy with these agents. The rapid increase in clinical toxicity at doses greater than 550 mg/m(2) of doxorubicin (DOX) has made this dose the limiting one in order to avoid DOX-induced cardiac failure. However, arbitrary dose limitation is inadequate because of variability of individual tolerance. Decreasing myocardial concentrations of anthracyclines (ANT) and their metabolites and schedule modification of administration can reduce anthracycline cardiotoxicity. Anthracycline structural analogues such as epirubicin, idarubicin and mitoxantrone have been used in clinical practice. In addition, the liposomal ANT, which can be incorporated into a variety of liposomal preparations, are a new class of agents that may permit more specific organ targeting of ANT, thereby producing less cardiac toxicity. Much interest has focused on the administration of ANT in conjunction with another agent that will selectively attenuate the cardiotoxicity. As is known, the ANT chelate iron and the DOX-iron complex catalyzes the formation of extremely reactive hydroxyl radicals. Many agents, such as dexrazoxane (DEX), able to remove iron from DOX, have been investigated as anthracycline cardioprotectors. Clinical trials of DEX have been conducted in children and significant short-term cardioprotection with no evidence of interference with antitumor activity has been demonstrated. Whether long-term cardiac toxicity will also be avoided in surviving patients has not yet been determined.

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“…Epirubicin (4'-epidoxorubicin) and pirarubicin (4'-O-tetrahydropyranyldoxorubicin) have been brought into routine clinical usage after it was observed that they produced less cardiotoxicity than doxorubicin and daunorubicin, the reference molecules, in both preclinical models and early clinical trials (Ganzina, 1983;Maehara et al, 1989;Herait et al, 1992). In addition, several strategies for reducing cardiotoxicity of anthracyclines have been proposed, including the administration of a-tocopherol (Julicher et al, 1986;Mimnaugh et al, 1981), N-acetylcysteine (Villani et al, 1990), glutathione (Villani et al, 1990), and ICRF-187 or dexrazoxane (Herman & Ferrans, 1986;Speyer et al, 1988). This last molecule has been shown to provide a prolonged protection against anthracycline cardiotoxicity in rabbits and dogs (Herman & Ferrans, 1986;Herman et al, 1988) and to prevent the doxorubicin-induced decrease of the left ventricular ejection fraction in human subjects (Speyer et al, 1988;.…”

Section: Introductionmentioning

confidence: 99%

Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention

Pouna

Bonoron‐Adèle

Gouverneur

et al. 1996

British J Pharmacology

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1 In order to develop a predictive model for the preclinical evaluation of anthracycline cardiotoxicity and the means of preventing it, we have studied the functional parameters of perfused hearts isolated from rats receiving repeated doses of several anthracyclines. 2 The anthracyclines studied were doxorubicin, epirubicin, pirarubicin and daunorubicin, and we also studied a liposomal formulation of daunorubicin (DaunoXome) and the co-administration of dexrazoxane (ICRF-187) and doxorubicin. 3 Anthracyclines were administered i.p. at equimolar doses corresponding to 3 mg kg-' per injection of doxorubicin, every other day for a total of six doses. Dexrazoxane was used at the dose of 30 mg kg-' per injection and was administered either 30 min before or 30 min after doxorubicin. We evaluated any general toxicity towards the animals as well as alterations of left ventricular contractility and relaxation ex vivo.4 Epirubicin and daunorubicin were significantly less cardiotoxic than doxorubicin, and neither pirarubicin nor DaunoXome caused significant alterations in cardiac function. There was a direct relationship between the decrease in cardiac contractility or relaxation and anthracycline accumulation in the heart, evaluated after the same treatment schedule. 5 Dexrazoxane induced a significant protection against doxorubicin-induced cardiac toxicity when administered 30 min before doxorubicin, whereas this protection was ineffective when administered 30 min after doxorubicin. Direct perfusion of DaunoXome in isolated hearts of untreated animals resulted in a 12-fold reduction of the accumulation of daunorubicin in heart tissue as compared to the perfusion of free daunorubicin, and did not cause alterations in cardiac function at a dosage for which free daunorubicin induced major alterations. 6 The isolated perfused rat heart appears to be a valuable model for screening of new anthracyclines and of strategies for circumventing anthracycline cardiotoxicity.

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Effect of Glutathione and N-Acetylcysteine on in Vitro and in VIVO Cardiac Toxicity of Doxorubicin

Cited by 30 publications

References 16 publications

Chemotherapy-Induced Weakness and Fatigue in Skeletal Muscle: The Role of Oxidative Stress

Chemotherapy-Induced Weakness and Fatigue in Skeletal Muscle: The Role of Oxidative Stress

Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood

Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention

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