Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart

Temma, Kyosuke; Akera, Tai; Chugun, Akihito; Kondo, Hiroshi; Hagane, Kazuhiko; Hirano, Shin‐ichi

doi:10.1016/0014-2999(93)90951-d

Cited by 29 publications

(18 citation statements)

References 26 publications

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“…In other studies, the effects of epirubicin were identical (Vile & Winterbourn, 1989;Hirano et al, 1994) or less pronounced (Llesuy et al, 1985) than those of doxorubicin. Similarly, pirarubicin has been shown to be less cardiotoxic than doxorubicin in two studies (Temma et al, 1993;Hirano et al, 1994) and more cardiotoxic in a third one (Del Tacca et al, 1987). Discrepancies were also found for daunorubicin, which was shown either less cardiotoxic (De Jong et al, 1993) or more cardiotoxic (Vile & Winterbourn, 1989) than doxorubicin.…”

Section: Discussionmentioning

confidence: 97%

“…The measure of left ventricular ejection fraction is a clinical evaluation of myocardial contractility and is routinely used to monitor anthracycline therapy in human subjects (Basser & Green, 1993), whereas endomyocardial biopsy remains far from routine clinical use. Numerous models have been developed for the understanding of anthracycline cardiotoxicity, using myocardial cells (Jiang et al, 1994), papillary muscles (Lee et al, 1991), microsomes (Vile & Winterbourn, 1989;Ondrias et al, 1990), mitochondria (Solem & Wallace, 1993), isolated atria (Monti et al, 1986;Temma et al, 1993) or isolated hearts directly perfused with anthracyclines (Pelikan et al, 1986;Rabkin, 1983;Del Tacca et al, 1987;Pouna et al, 1995). The interest of these models is to identify the possible targets of anthracyclines in the heart and to understand the mechanisms of cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…However, they are of little interest for the prediction of heart function impairment induced by anthracyclines. High drug concentrations are often required for the production of significant effects on most of these models (Lee et al, 1991;Temma et al, 1993;Solem & Wallace, 1993;Jiang et al, 1994), whereas 10 to 100 fold less drug concentrations are sufficient to obtain alterations of cardiac function in animals and man. As a consequence, it is not possible to relate the observations made on these experimental models to the in vivo situation and to use them as predictors of the clinical toxicity.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Consistent with these concepts, we observed that doxorubicintreatment of the rat results in a significant reduction of the caffeine-induced contraction in skinned muscle fiber preparations, although Ca 2+ sensitivity was unchanged [7]. Similar changes, namely the prolongation of the time to the peak of twitch tension and the reduction of postrest contraction were observed in heart muscle preparations isolated from non-drug-treated rats or guinea pigs, and exposed a relatively long period to doxorubicin in vitro [10,18,29]. These results indicate that cardiac dysfunctions produced by doxorubicin in vitro resemble those induced by the treatment of animals in vivo.…”

mentioning

confidence: 75%

“…A pair of platinum electrodes was used for electrical-field stimulation. Isometric force of contraction was continuously recorded using a force displacement transducer (TB-651: Nihon Kohden, Tokyo, Japan) and a pen recorder (WI621G: Nihon Kohden, Tokyo, Japan) with the resting tension adjusted to 1.0 g [7,29]. After a 90-to 120-min equilibration period with 2-Hz stimulation, the stimulator was turned off for 60 sec.…”

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Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

et al. 2008

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ABSTRACT. We reported previously that doxorubicin, an anticancer agent that has an anthracycline structure, alters Ca 2+ releasing and uptake mechanisms in the sarcoplasmic reticulum of myocardial cells. These effects of doxorubicin are apparently related to its cardiotoxicity. Mitoxantrone is a similar anticancer agent with an anthracenedion structure that has been shown to be significantly less cardiotoxic. In the present study, the effects of mitoxantrone on the functions of the sarcoplasmic reticulum were examined in isolated muscle preparations obtained from the guinea-pig heart. In electrically-stimulated left atrial muscle preparations, incubation in vitro for 4 hr with 30 or 100 µM mitoxantrone significantly prolonged the time to the peak of twitch tension, markedly increased the developed tension observed at lower stimulation frequencies, thereby attenuating the slope of positive force-frequency relationships, and increased the postrest contraction observed after a 60-sec quiescent period. In myocytes isolated from ventricular muscles, 30 µM mitoxantrone increased the peak and the size of intracellular Ca 2+ concentrations ([Ca 2+ ]i), and prolonged the time to peak [Ca 2+ ]i. In skinned muscle fiber preparations obtained from the left ventricular muscle, 30 µM mitoxantrone significantly increased the caffeine-induced contraction without affecting the Ca 2+ sensitivity of contractile proteins. These results suggest that mitoxantrone enhances Ca 2+ release from the sarcoplasmic reticulum in isolated atrial muscle preparations obtained from the guinea-pig heart. Apparent enhancement of the sarcoplasmic reticulum functions, in contrast to anthracyclines that has been shown to suppress these functions, seems to explain the relative lack of marked cardiotoxicity of mitoxantrone. KEY WORDS: caffeine-induced contraction, Ca 2+ release and uptake by sarcoplasmic reticulum, inotropic effects, intracellular Ca 2+ concentration, mitoxantrone.J. Vet. Med. Sci. 70(3): 255-264, 2008 Anthracyclines are efficacious anti-tumor agents; however, their clinical usefulness is limited by serious cardiotoxic effects. Mitoxantrone, an anthracenedion derivative, has been synthesized in an attempt to develop an agent that has a reliable anticancer activity without the compromising cardiotoxic effects [9,35].Human as well as animal studies demonstrated that the cardiotoxic effects of mitoxantrone are significantly less severe at clinically equivalent anticancer doses compared to those observed with anthracyclines [2,9,11,13,20,22,33].We reported previously [7] that in vivo treatment of rats with doxorubicin results in a prolongation of the time to the peak of twitch tension, a reduction of the developed tension observed at lower stimulation frequencies and an attenuation of the postrest contraction (contraction that is evoked by the first stimulus after a brief quiescent period) observed in electrically-stimulated heart muscle preparations obtained from the drug-treated animals. These changes developed slowly with time aft...

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Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin

Pouna

Bonoron‐Adèle

Gouverneur

et al. 1995

Cancer Chemother. Pharmacol.

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We have compared the cardiotoxicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10(-6) and 10(-5) M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10(-6) M. At 10(-5) M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4-5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.

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Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart

Cited by 29 publications

References 26 publications

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

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

Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin

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