Dexrazoxane in the Prevention of Doxorubicin-Induced Cardiotoxicity

Seifert, Charles F.; Nesser, Mary Ellen; Thompson, Dennis F.

doi:10.1177/106002809402800912

Cited by 126 publications

(83 citation statements)

References 37 publications

(4 reference statements)

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“…Numerous research have focused on prevention of ADR-induced cardiac injuries [2]. Co-administration of cardioprotective agents, which do not attenuate the anticancer activity of ADR, is one approach [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Daosukho

Chen

Noel

et al. 2007

Free Radical Biology and Medicine

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Cardiac injury is a major complication for oxidative stress-generating anticancer agents exemplified by Adriamycin (ADR). Recently, several histone deacetylase inhibitors (HDACIs) including phenylbutyrate (PBA) have shown promise in the treatment of cancer with little known toxicity to normal tissues. PBA has been shown to protect against oxidative stress in normal tissues. Here, we examined whether PBA might protect heart against ADR toxicity in a mouse model. The mice were i.p. injected with ADR (20 mg/kg). PBA (400 mg/kg/day) was i.p. injected one day before and daily after the ADR injection for two days. We found that PBA significantly decreased the ADR-associated elevation of serum lactase dehydrogenase (LDH) and creatine kinase (CK) activities, and diminished ADR-induced ultrastructual damages of cardiac tissue by more than 70%. Importantly, PBA completely rescued ADR-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening, and increased cardiac MnSOD protein and activity. Our results reveal a previously unrecognized role of HDACIs in protecting against ADR-induced cardiac injury, and suggest that PBA may exert its cardioprotective effect, in part, by the increase of MnSOD. Thus, combining HDACIs with ADR could add a new mechanism to fight cancer while simultaneously decrease ADR-induced cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Daosukho

Chen

Noel

et al. 2007

Free Radical Biology and Medicine

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“…It is thought that doxorubicin, through its semiquinone metabolite, generates superoxide anion and superhydroxide free radicals by using intracellular iron as a cofactor. 8 Because the heart is relatively deficient in those enzymes responsible for clearing free radicals (ie, superoxide dismutase, catalase, and glutathione peroxidase), 6 the administration of doxorubicin may lead to significant lipid peroxidation and destruction of mitochondrial membranes.…”

mentioning

confidence: 99%

Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

1999

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Abstract-Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We examined the effects of this agent on the expression of the natriuretic peptide (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while exerting no effect on BNP mRNA levels or promoter activity. This represents the first identification of the NP genes as targets of doxorubicin toxicity in the myocardial cell. This inhibition operates predominantly at a transcriptional locus and has more potent effects on BNP versus ANP secretion/gene expression.

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“…The most important and probable seems to be the mechanism based on the generation by doxorubicin of oxidative stress in the heart muscle and stimulation of apoptosis in cardiomyocytes (14). Because of poor antioxidant protection in cardiac myocytes (low concentration of superoxide dismutase, catalase and glutathione peroxidase) reactive oxygen species cause lipid peroxidation and mitochondrial destruction (15). There are some ways of reducing the cardiotoxicity of doxorubicin: monitoring chemotherapy, modifying the schedule of administration, patients selection considering Figure 2.…”

Section: Discussionmentioning

confidence: 99%

Effects of Carnosine on the Toxicity of Doxorubicin in Rabbits and Mice

et al. 2003

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The aim of this study was to establish the effect of naturally occurring antioxidant -carnosine -on the doxorubicin induced cardiotoxicity in a rabbit model. For this purpose we evaluated the influence of doxorubicin administration alone and in a combined therapy with carnosine on the haemodynamic parameters and on the degree of cardiac muscle cells alterations in rabbits. The rabbits were divided into four groups. One group of rabbits was injccted with doxorubicin in a dose of 2 mg kg -1 weekly for 7 weeks to induce congestive heart failure. Another group of rabbits received the same doses of doxorubicin simultaneously with carnosine in a dose of 100 mg kg 1 p.o. daily for 9 weeks. Administration of carnosine was started 1 week prior to the first dose of doxorubicin and was ended one week after the administration of the last dose of doxorubicin. The control groups of animals received 0.9% NaCl and carnosine alone. The following haemodynamic parameters were estimated: heart rate, mean arterial pressure, cardiac index, stroke index and total peripheral resistance. Registration of the haemodynamic parameters in rabbits was performed by Doppler method. Carnosine normalised the values of mean arterial pressure in rabbits receiving doxorubicin, and increased the values of cardiac index and stroke index. The influence of carnosine on total peripheral resistance was not statistically significant, but there was a decreasing tendency. The degree of cardiac muscle cell alterations was examined by light microscopy using Mean Total Score technique. The histopathological studies revealed smaller damage of cardiac muscle in rabbits which received doxorubicin and carnosine, in comparison to animals receiving doxorubicin alone. Carnosine seems to be car dioprotective during doxorubicin administration.

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Dexrazoxane in the Prevention of Doxorubicin-Induced Cardiotoxicity

Cited by 126 publications

References 37 publications

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

Effects of Carnosine on the Toxicity of Doxorubicin in Rabbits and Mice

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