The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925

Hasinoff, Brian B.; Kala, Subbarao V.

doi:10.1007/bf01975717

Cited by 20 publications

(16 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The protective mechanisms and pharmacological properties of dexrazoxane that are responsible for its effect on mortality have not been clarified in this study. The ability of dexrazoxane and its 1-ring-opened hydrolysis intermediates and its 2-ring-opened hydrolysis product to remove iron from transferrin and ferritin, and from anthracycline-iron complexes, has been demonstrated in vitro [Hasinoff and Kala, 1993;Buss and Hasinoff, 1993]. Consistent with these findings, in vivo studies have shown that while dexrazoxane inhibits doxorubicin-induced lipid peroxidation in mouse cardiac microsomal enzymes by 65%, its final hydrolysis product causes complete inhibition of lipid peroxidation [Hüsken et al, 1995].…”

Section: Discussionmentioning

confidence: 74%

Dexrazoxane-induced reduction in mortality in mice subjected to severe forebrain ischemia

Rodríguez¹,

Gerson

Santiago‐Mejia³

2000

Drug Dev. Res.

View full text Add to dashboard Cite

In this study we determined whether dexrazoxane reduces mortality in mice subjected to bilateral sequential common carotid artery sectioning. Under pentobarbital anesthesia, the left common carotid artery was ligated and sectioned. In one group of experiments, 32 days later mice were injected i.p. with dexrazoxane (16, 64, 256 mg/kg) 30 min before being reanesthetized to ligate and section the right common carotid artery. In the second group of animals dexrazoxane was given, at the same doses, 15 min after ligating and sectioning the right common carotid artery. Dexrazoxane significantly decreased the cumulated mortality rate compared with controls. When given 30 min before the second surgery dexrazoxane was active only at doses of 256 mg/kg. In contrast, when given 15 min after the second ischemic insult the protective effect of dexrazoxane was already evident at 16 mg/kg, increasing dose‐dependently with an almost complete protection at 256 mg/kg during the first 24 h of observation; some degree of protection persisted up to day 4. One possible explanation for this striking difference in efficacy is that dexrazoxane passes through a compromised but not through an intact blood–brain barrier. We conclude that dexrazoxane has important neuroprotective properties against brain ischemia and that its clinical trial in stroke should be considered. Drug Dev. Res. 51:149–152, 2000. © 2001 Wiley‐Liss, Inc.

show abstract

Section: Discussionmentioning

confidence: 74%

Dexrazoxane-induced reduction in mortality in mice subjected to severe forebrain ischemia

Rodríguez¹,

Gerson

Santiago‐Mejia³

2000

Drug Dev. Res.

View full text Add to dashboard Cite

show abstract

“…This molecule provides a prolonged protection against anthracycline cardiotoxicity, and not only a delay of the appearance of cardiac alterations (Herman & Ferrans, 1986). The mechanism by which dexrazoxane protects the heart against anthracycline toxicity is not well understood but is thought to involve metal chelation (Hasinoff & Kala, 1993). Indeed, dexrazoxane administered systemically is taken up intracellularly and hydrolysed to its diacid, diamide metabolite, (Hasinoff et al, 1990), which is a strong ion metal chelator, with a structure similar to EDTA (Thomas et al, 1993).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…In addition, DEX and ADR-925 chelate Fe 3+ from transferrin and ferritin [88]. Therefore DEX can, in part, prevent DOXcardiotoxicity by depleting iron from storage and transport proteins [88]. This means that ADR-925 removes Fe 3+ more powerfully than does the DOX.…”

Section: Iron-chelatorsmentioning

confidence: 96%

“…In the myocardial cells, DEX is hydrolyzed into an open-ring form ADR-925 (ICRF-198) that is a strong metal ion chelating extent as ADR-925, Fe 3+ from its complex with DOX [86]. In addition, DEX and ADR-925 chelate Fe 3+ from transferrin and ferritin [88]. Therefore DEX can, in part, prevent DOXcardiotoxicity by depleting iron from storage and transport proteins [88].…”

Section: Iron-chelatorsmentioning

confidence: 98%

Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood

Iarussi¹,

Indolfi²,

Casale³

et al. 2001

CMC

View full text Add to dashboard Cite

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.

show abstract

The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925

Cited by 20 publications

References 39 publications

Dexrazoxane-induced reduction in mortality in mice subjected to severe forebrain ischemia

Dexrazoxane-induced reduction in mortality in mice subjected to severe forebrain ischemia

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

Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood

Contact Info

Product

Resources

About