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

Pouna, Paul; Bonoron‐Adèle, Simone; Gouverneur, G.; Tariosse, Liliane; Besse, P; Robert, Jacques

doi:10.1111/j.1476-5381.1996.tb15326.x

Cited by 60 publications

(44 citation statements)

References 47 publications

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“…We have recently developed a functional ex vivo model for the rapid evaluation of the cardiotoxicity of anthracyclines, and this model was shown to correctly predict for the comparative cardiotoxicity of the various molecules presently marketed including the known activity of dexrazoxane as a cardioprotector Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin (Pouna et al, 1996). This model consists in treating rats every two days for 11 days with anthracyclines, at the dose of 3 mg kg Ð1 per day (18 mg kg Ð1 cumulative dose), intraperitonealy (i.p.).…”

mentioning

confidence: 99%

Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin

Platel

Bonoron‐Adèle

Dix³

et al. 1999

Br J Cancer

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Cardiotoxicity represents the major side-effect limiting the clinical use of anthracyclines, especially doxorubicin, in cancer chemotherapy. The use of non-toxic prodrugs, or of liposome-encapsulated drugs, allows a better targeting of the tumours and may, therefore, improve the tolerance to the treatment. Using the model of isolated perfused rat heart, we have evaluated the cardiotoxicity of a novel prodrug of doxorubicin, HMR-1826, which consists of the association of doxorubicin to glucuronic acid. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by HMR-1826 to those induced by doxorubicin and Doxil, a liposomal form of doxorubicin. HMR-1826 was administered intravenously every other day for 11 days at doses of 50–200 mg kg −1 per injection while doxorubicin was administered according to the same protocol at doses of 1–3 mg kg −1 per injection. Doxorubicin strongly decreased the cardiac functional parameters at the doses of 2.5 and 3 mg kg −1 per injection. Doxil (3 mg kg −1 ) and HMR-1826 (50–150 mg kg −1 ) were largely devoid of cardiotoxicity. HMR-1826 only induced significant alterations of the cardiac function at the highest dose used (200 mg kg −1 per injection). These alterations were much lower than those of doxorubicin at 2.5 mg kg −1 per injection, despite similar general toxicity symptoms (weight loss, nose bleeding and diarrhoea) at these respective doses. Thus, HMR-1826 appeared about 100-fold less cardiotoxic than doxorubicin. © 1999 Cancer Research Campaign

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confidence: 99%

Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin

Platel

Bonoron‐Adèle

Dix³

et al. 1999

Br J Cancer

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“…High activities of daunorubicin carbonyl reduction have also been found in all blood cells, especially in leukocytes (Huffman et al 1972). In a recent study, only daunorubicinol was found in the heart tissue two days after the last ip administration of daunorubicin into intact animals, whereas daunorubicinol found in heart extracts after isolated perfusion represented only 13-15% of the unchanged drug (Pouna et al 1996). In other studies, doxorubicin concentration in the heart reached its peak value one hour after injection of doxorubicin (Peters et al 1981;Del Tacca et al 1985;Doroshow et al 1981), whereas doxorubicinol was undetectable or present in very low concentrations.…”

Section: Discussionmentioning

confidence: 98%

“…In view of these facts it is plausible that under a therapeutic regimen most of the daunorubicinol formed in respective tissues may reach the cardiac tissue via the circulation and add to the 13-hydroxy metabolites of daunorubicin that produces the heart itself. Although cellular uptake by diffusion seems difficult, selective accumulation of the relative polar 13-hydroxy metabolites has frequently been observed after chronic administration Del Tacca et al 1985;Peters et al 1981;Rossini et al 1986;Pouna et al 1996), raising the question for the existence of a more or less specific transport system in the cardiac tissue.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of cardiac dysfunction may relate to ATPase inhibition, since doxorubicinol, but not doxorubicin, is a potent inhibitor of Ca2+-Mg*+-ATPase of sarcoplasmic reticulum, Mg2+-ATPase of mitochondria, and Na+-K+-ATPase activity of sarcolemma (Moore et al 1977;Unverferth et al 1982;Olson et al 1988;Boucek et al 1987). In addition, it should be noted that only daunorubicinol but not daunorubicin was found in the heart tissue two days after daunorubicin treatment in animal studies (Pouna et al 1996). The metabolism of 13-keto anthracyclines, for which daunorubicin serves as a reference molecule ( fig.…”

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Carbonyl Reduction of Daunorubicin in Rabbit Liver and Heart

Pröpper

Maser

1997

Pharmacology & Toxicology

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A major problem of anthracycline anticancer treatment are the cardiotoxic side effects associated with drug therapy. Increased attention has recently been focused on the 13-hydroxy anthracycline metabolites which are formed by carbonyl reduction of the parent drug as contributing to cardiotoxicity. By using daunorubicin as a reference molecule, our study was designed to quantitatively evaluate and compare the extent of anthracycline carbonyl reduction of liver and heart at the physiological important pH 7.4, and to identify the enzyme@) involved under these conditions. The present kinetic data indicate that only one single enzyme system is active in cytosol of both tissues. According to its specific inhibition by quercitrin and the failure of a barbiturate to affect activity the enzyme responsible for daunorubicin carbonyl reduction in these fractions is carbonyl reductase (EC 1.1.1.184). Since the KM values differ significantly from each other, it is suggested that liver and heart express different isoforms of this enzyme. We failed to detect any specific daunorubicin carbonyl reductase activity in both microsomal fractions. Intrinsic clearance values revealed that liver has obviously 350-times the capacity of total 13-hydroxy metabolite formation compared to heart. This indicates that under a therapeutic regimen 13-hydroxy anthracyclines of hepatic origin would add to the metabolites that are produced by the heart itself. The prevention of these metabolites may represent a potential approach for enhancing the safety and efficacy of anthracycline chemotherapy.

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“…This may have some clinical rel-evance in view of the fact that special new particulate formulations of anthracyclines may lead to a decrease or an increase in the level of biotransformation to the reduced metabolite. We have used the model of isolated perfused rat heart that we have recently set up (Pouna et al 1996) and validated under various circumstances (Platel et al 1999a(Platel et al , b & 2000. We show in this paper that daunorubicinol is a much less cardiotoxic than daunorubicin and can no longer be considered as responsible for the cardio toxicity of daunorubicin.…”

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confidence: 99%

Role of Daunorubicinol in Daunorubicin‐Induced Cardiotoxicity as Evaluated with the Model of Isolated Perfused Rat Heart

Platel¹,

Bonoron‐Adèle²,

Robert³

2001

Pharmacology & Toxicology

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Cardiotoxicity is the major side-effect and limits the clinical use of the anthracyclines, doxorubicin and daunorubicin. A special problem is raised by the metabolites of these drugs, the amount of which may vary according to drug combinations and formulations. Doxorubicinol, the 13-dihydroderivative of doxorubicin, has been shown to be more cardiotoxic than unchanged doxorubicin. Daunorubicinol has been assumed also to be more cardiotoxic than unchanged daunorubicin but its direct effect on cardiac function has never been evaluated in preclinical models. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by daunorubicinol to those induced by daunorubicin, using the model of the isolated perfused rat heart. After treatment of rats with 6 doses of 3 mg/kg intraperitoneally, daunorubicin strongly decreased the cardiac functional parameters, while daunorubicinol did not induce cardiotoxicity. Both treatments induced a similar accumulation of daunorubicinol in the myocardium, while daunorubicin was only found in the hearts of rats treated with this drug. Direct perfusion of the hearts of untreated rats with both drugs at 10 mM induced a depression in heart function, but daunorubicin induced a progressive increase in diastolic pressure, reflecting the difficulties encountered by the heart to maintain its activity in the presence of this drug, while daunorubicinol did not. We conclude that daunorubicinol is not responsible for the important cardiac toxicity of daunorubicin.

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

Cited by 60 publications

References 47 publications

Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin

Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin

Carbonyl Reduction of Daunorubicin in Rabbit Liver and Heart

Role of Daunorubicinol in Daunorubicin‐Induced Cardiotoxicity as Evaluated with the Model of Isolated Perfused Rat Heart

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