Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ADR-529) on iron-catalyzed lipid peroxidation

ADR-529 [(+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane], a nonpolar, cyclic analogue of EDTA, protects against anthracycline cardiotoxicity in vivo. The protective mechanism presumably involves chelation of iron by a hydrolysis product of ADR-529, thus preventing the formation of reactive iron/oxygen species which can damage membrane lipids. We investigated the effects of ADR-529 and its hydrolysis products (the tetraacid and the diacid diamide) on NADPH- and ADP-Fe(3+)-dependent lipid peroxidation of rat liver microsomes and liposomes in the presence of cytochrome P-450 reductase. Hydrolyzed ADR-529 products caused inhibition of lipid peroxidation when in excess of the iron concentration. However, no inhibition of lipid peroxidation was detected by similar concentrations of nonhydrolyzed ADR-529. Microsomes did not affect the inhibition of lipid peroxidation, suggesting that rat liver microsomes do not hydrolyze ADR-529. Similarly, the diacid diamide hydrolysis product of ADR-529 inhibited ferritin- and adriamycin-iron-dependent liposomal lipid peroxidation in a concentration-dependent manner. No correlation between partially reduced oxygen species (O2.- and .OH; as measured by electron spin resonance) and lipid peroxidation (as assayed by malondialdehyde formation) was observed, suggesting that liposomal lipid peroxidation was strictly an iron-dependent phenomenon. These results suggest that inhibition of lipid peroxidation by iron chelation may be related to the protective effects of ADR-529 on in vivo anthracycline toxicity.     

Metabolism of the one-ring open metabolites of the cardioprotective drug dexrazoxane to its active metal-chelating form in the rat.

Dexrazoxane (ICRF-187) is clinically used as a doxorubicin cardioprotective agent and may act by preventing iron-based oxygen free radical damage through the iron-chelating ability of its fully hydrolyzed metabolite ADR-925 (N,N'-[(1S)-1-methyl-1,2-ethanediyl]-bis[(N-(2-amino-2-oxoethyl)]glycine). Dexrazoxane undergoes initial metabolism to its two one-ring open intermediates and is then further metabolized to its active metal ion-binding form ADR-925. The metabolism of these intermediates to the ring-opened metal-chelating product ADR-925 has been determined in a rat model to identify the mechanism by which dexrazoxane is activated. The plasma concentrations of both intermediates rapidly decreased after their i.v. administration to rats. A maximum concentration of ADR-925 was detected 2 min after i.v. bolus administration, indicating that these intermediates were both rapidly metabolized in vivo to ADR-925. The kinetics of the initial appearance of ADR-925 was consistent with formation rate-limited metabolism of the intermediates. After administration of dexrazoxane or its two intermediates, ADR-925 was detected in significant levels in both heart and liver tissue but was undetectable in brain tissue. The rapid rate of metabolism of the intermediates was consistent with their hydrolysis by tissue dihydroorotase. The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These studies showed that the two one-ring open metabolites of dexrazoxane were rapidly metabolized in the rat to ADR-925, and thus, these results provide a mechanism by which dexrazoxane is activated to its active metal-binding form.     

Dihydroorotase catalyzes the ring opening of the hydrolysis intermediates of the cardioprotective drug dexrazoxane (ICRF-187).

The enzyme kinetics of the hydrolysis of the one-ring open metabolites of the antioxidant cardioprotective agent dexrazoxane [ICRF-187; (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane] to its active metal ion binding form ADR-925 [N,N'-[(1S)-1-methyl-1,2-ethanediyl]bis[N-(2-amino-2-oxoethyl)glycine] by dihydroorotase (DHOase) has been investigated by high-performance liquid chromatography (HPLC). A spectrophotometric detection HPLC assay for dihydroorotate was also developed. Dexrazoxane is clinically used to reduce the iron-based oxygen free radical-mediated cardiotoxicity of the anticancer drug doxorubicin. DHOase was found to catalyze the ring opening of the metabolites with an apparent V(max) that was 11- and 27-fold greater than its natural substrate dihydroorotate. However, the apparent K(m) for the metabolites was 240- and 550-fold larger than for dihydroorotate. This report is the first that DHOase might be involved in the metabolism of a drug. Furosemide inhibited DHOase, but the neutral 4-chlorobenzenesulfonamide did not. Because dihydroorotate, the one-ring open metabolites, and furosemide all have a carboxylate group, it was concluded that a negative charge on the substrate strengthened binding to the positively charged active site. The presence of DHOase in the heart may explain the cardioprotective effect of dexrazoxane. Thus, dihydropyrimidinase and DHOase acting in succession on dexrazoxane and its metabolites to form ADR-925 provide a mechanism by which dexrazoxane is activated to exert its cardioprotective effects. The ADR-925 thus formed may either remove iron from the iron-doxorubicin complex, or bind free iron, thus preventing oxygen radical formation.     

The metabolites of the cardioprotective drug dexrazoxane do not protect myocytes from doxorubicin-induced cytotoxicity

The clinically approved cardioprotective agent dexrazoxane (ICRF-187) and two of its hydrolyzed metabolites (a one-ring open form of dexrazoxane and ADR-925) were examined for their ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Dexrazoxane may protect against doxorubicin-induced damage to myocytes through its strongly metal-chelating hydrolysis product ADR-925, which could act by displacing iron bound to doxorubicin or chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage. The results of this study showed that whereas dexrazoxane was able to protect myocytes from doxorubicin-induced lactate dehydrogenase release, neither of the metabolites displayed any protective ability. Dexrazoxane also reduced apoptosis in doxorubicin-treated myocytes. The ability of dexrazoxane and its three metabolites to displace iron from a fluorescence-quenched trapped intracellular iron-calcein complex was also determined to see whether the metabolites were taken up by myocytes. Although ADR-925 was taken up in the absence of calcium in the medium, in the presence of calcium, its uptake was greatly slowed, presumably because it formed a complex with calcium. Both of the one-ring open metabolites were taken up by myocytes and displaced iron from its complex with calcein. These results suggest either that the anionic metabolites do not have the same access to iron pools in critical cellular compartments, that their uptake is slowed in the presence of calcium, or, less likely, that dexrazoxane protects by some other mechanism.     

Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone

Background and purpose:The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS).Experimental approach:The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation.Key results:SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU.Conclusions and implications:This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.British Journal of Pharmacology (2008) 155, 138-148; doi:10.1038/bjp.2008.236; published online 9 June 2008.     

Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy

Anthracycline-induced cardiomyopathy is a major problem in anti-cancer therapy. The only approved agent for alleviating this serious dose limiting side effect is ICRF-187 (dexrazoxane). The current thinking is that the ring-opened hydrolysis product of this agent, ADR-925, which is formed inside cardiomyocytes, removes iron from its complexes with anthracyclines, hereby reducing the concentration of highly toxic iron–anthracycline complexes that damage cardiomyocytes by semiquinone redox recycling and the production of free radicals. However, the 2 carbon linker ICRF-187 is also is a catalytic inhibitor of topoisomerase II, resulting in the risk of additional myelosuppression in patients receiving ICRF-187 as a cardioprotectant in combination with doxorubicin. The development of a topoisomerase II-inactive iron chelating compound thus appeared attractive. In the present paper we evaluate the topoisomerase II-inactive 3 carbon linker bisdioxopiperazine analog ICRF-161 as a cardioprotectant. We demonstrate that this compound does chelate iron and protects against doxorubicin-induced LDH release from primary rat cardiomyocytes in vitro, similarly to ICRF-187. The compound does not target topoisomerase II in vitro or in cells, it is well tolerated and shows similar exposure to ICRF-187 in rodents, and it does not induce myelosuppression when given at high doses to mice as opposed to ICRF-187. However, when tested in a model of chronic anthracycline-induced cardiomyopathy in spontaneously hypertensive rats, ICRF-161 was not capable of protecting against the cardiotoxic effects of doxorubicin. Modulation of the activity of the beta isoform of the topoisomerase II enzyme by ICRF-187 has recently been proposed as the mechanism behind its cardioprotection. This concept is thus supported by the present study in that iron chelation alone does not appear to be sufficient for protection against anthracycline-induced cardiomyopathy.     

The antitumor anthracyclines doxorubicin and daunorubicin do not inhibit cell growth through the formation of iron-mediated reactive oxygen species

The use of the anthracycline anticancer drugs doxorubicin and daunorubicin is limited by what is thought to be an iron-based oxygen radical-derived dose-dependent cardiotoxicity. The anthracyclines are also DNA topoisomerase (Topo) II poisons. It is not known if iron-mediated formation of reactive oxygen species (ROS) by the anthracyclines or their Topo II inhibitory effects are responsible for their cell growth-inhibitory effects. Experiments to test these two alternatives were carried out using a CHO-derived cell line (DZR) that was highly resistant to dexrazoxane through a Thr48IIe mutation in Topo IIalpha. The clinically used cardioprotective agent dexrazoxane likely exerts its cardioprotective effects through the chelating ability of its hydrolysis product ADR-925, an analog of EDTA. Dexrazoxane is also a cell growth inhibitor that acts through its ability to inhibit the catalytic activity of Topo II. Thus, the DZR cell line allowed us to examine the cell growth-inhibitory effects of doxorubicin and daunorubicin in the presence of dexrazoxane without the confounding effect of dexrazoxane inhibiting cell growth. The growth-inhibitory effects of neither doxorubicin nor daunorubicin were affected by pretreating DZR cells with dexrazoxane. In contrast, under similar conditions, dexrazoxane strongly protected rat cardiac myocytes from doxorubicin-induced lactate dehydrogenase release. In conclusion, the anthracyclines do not inhibit the growth of DZR cells through the generation of iron-mediated formation of ROS.     

Recent advances in the prevention of anthracycline cardiotoxicity in childhood

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.     

In vitro evidence for direct complexation of ADR-529/ICRF-187 [(+)-1,2-bis-(3,5-dioxo-piperazin-1-yl)propane] onto an existing ferric-anthracycline complex.

ADR-529 protects against anthracycline cardiotoxicity, possibly by preventing free radical induction. We hypothesize that this occurs by ADR-529 forming a ternary anthracycline-iron-ADR-529 complex. This study used 200-MHz Fourier-transformed NMR to demonstrate the ability of ADR-529 to do this. Peak assignments were by proton-correlated spectroscopy and proton-carbon heteronuclear-correlated spectroscopy. Ga3+ served as a probe for Fe3+, and D2O was the system solvent. Doxorubicin and epirubicin were the studied drugs. Proton spectra of multiple combinations (including pure standards as controls) were obtained. Both Ga3+ plus ADR-529 and Ga3+ plus doxorubicin showed evidence of complexation, as seen by appropriate peak shifts and changes in the associated coupling constants. Ga3+ plus ADR-529 plus epirubicin showed complexation different from that of Ga3+ plus ADR-529 or Ga3+ plus doxorubicin and consistent with the proposed structure. We conclude that ADR-529 would be able to form a ternary complex with an existing anthracycline-Fe3+ complex in an isolated aqueous environment.     

Examination of the mechanism(s) involved in doxorubicin-mediated iron accumulation in ferritin: studies using metabolic inhibitors, protein synthesis inhibitors, and lysosomotropic agents

Anthracyclines are potent anticancer agents, but their use is limited by cardiotoxicity at high cumulative doses. The mechanisms involved in anthracycline-mediated cardiotoxicity are still poorly understood, but numerous investigations have indicated a role for iron in this process. Our previous studies using neoplastic and myocardial cells showed that anthracyclines inhibit iron mobilization from the iron storage protein, ferritin, resulting in marked accumulation of ferritin-iron. Although the process of ferritin-iron mobilization is little understood, catabolism of ferritin by lysosomes may be a likely mechanism. Because anthracyclines have been shown to accumulate in lysosomes, this latter organelle may be a potential target for these drugs. The present study demonstrated, using native polyacrylamide gel electrophoresis-59Fe autoradiography, that ferritin-59Fe mobilization is an energy-dependent process that also requires protein synthesis. Depression of lysosomal activity via the enzyme inhibitors E64d [(2S,3S)-trans-epoxysuccinyl-l-leucylamido-2-methylbutane ethyl ester] and leupeptin or the lysosomotropic agents ammonium chloride, chloroquine, and methylamine resulted in a 3- to 5-fold increase in 59Feferritin accumulation compared with control cells. In addition, the proteasome inhibitors N-benzoyloxycarbonyl (Z)-Leu-Leuleucinal (MG132) and lactacystin also significantly increased 59Fe-ferritin levels compared with control cells. These effects of lysosomotropic agents or inhibitors of lysosomal activity were comparable with that observed with the anthracycline doxorubicin. Collectively, our study indicates a role for lysosomes and proteasomes in ferritin-iron mobilization, and this pathway is dependent on metabolic energy and protein synthesis. Furthermore, the lysosome/proteasome pathway may be a novel anthracycline target, inhibiting iron mobilization from ferritin that is essential for vital iron-requiring processes such as DNA synthesis.     

一例蒽环类药物心脏毒性的用药分析

蒽环类药物的剂量限制性心脏毒性限制了其在临床上的应用。本文就一例恶性淋巴瘤患者用药后出现的心脏毒性反应,对蒽环类药物心脏毒性的发生机制、危险因素、监测和防治等方面作一综述。     

Iron chelator research: past,present, and future

The occurrence of in vivo iron toxicity in the human body can be categorized into iron overload and non-iron overload conditions. Iron overload conditions are common in beta-thalassemia and hereditary hemochromatosis patients, and anthracycline mediated cardiotoxicity is an example of a non-iron overload condition in cancer patients, in which the toxicity is iron-dependent. While hundreds of iron chelators have been evaluated in animal studies, only a few have been studied in humans. Examples of iron chelator drugs are desferrioxamine (DFO), deferiprone (L1), and dexrazoxane (ICRF 187). The compound ICL670 has completed phase II clinical trials and a phase III trial is planned in 2003. Triapine is currently in phase II clinical trial as an anticancer agent. CP502, GT56-252, NaHBED, and MPB0201 are examples of new chelators in preclinical/clinical development. In the past decade, many new viable utilities for iron chelators have been reported. This includes the use of iron chelators as antiviral, photoprotective, antiproliferative, and antifibrotic agents. This review will focus on the status of drug development for the treatment of iron overload in patients with beta-thalassemia and the potential use of iron chelators in the prevention and treatment of other diseases.     

微小 RNA对阿霉素诱导心脏毒性保护作用的研究进展

阿霉素(DOX)是一种具有强效抗肿瘤作用的蒽环类抗生素,其临床应用因其心脏毒性而受到限制,但其发病机制仍未完全了解.近年来,许多研究提出微小RNA(miRNA)在DOX诱导心脏毒性过程中有重要作用,它可调节心肌细胞的凋亡、自噬相关基因表达稳定性,现就近期miRNA的研究结果,尤其是miRNA在DOX诱导心肌细胞损伤分子机制以及与上下游相关基因的调节作用做一综述.miRNA可能成为DOX心脏毒性新的诊断性生物学诊断指标,miRNA激动剂或拮抗剂和外源性miRNA模拟药可能成为今后治疗DOX所致心脏毒性的新靶点.     

Anthracycline cardiotoxicity

INTRODUCTION: Anthracyclines are widely prescribed anticancer agents that cause a dose-related cardiotoxicity, often aggravated by nonanthracycline chemotherapeutics or new generation targeted drugs. Anthracycline cardiotoxicity may occur anytime in the life of cancer survivors. Understanding the molecular mechanisms and clinical correlates of cardiotoxicity is necessary to improve the therapeutic index of anthracyclines or to identify active, but less cardiotoxic analogs. AREAS COVERED: The authors review the pharmacokinetic, pharmacodynamic and biochemical mechanisms of anthracycline cardiotoxicity and correlate them to clinical phenotypes of cardiac dysfunction. Attention is paid to bioactivation mechanisms that converted anthracyclines to reactive oxygen species (ROS) or long-lived secondary alcohol metabolites. Preclinical aspects and clinical implications of the "oxidative stress" or "secondary alcohol metabolite" hypotheses are discussed on the basis of literature that cuts across bench and evidence-based medicine. Interactions of anthracyclines with comorbidities or unfavorable lifestyle choices were identified as important cofactors of the lifetime risk of cardiotoxicity and as possible targets of preventative strategies. EXPERT OPINION: Anthracycline cardiotoxicity is a multifactorial process that needs to be incorporated in a translational framework, where individual genetic background, comorbidities, lifestyles and other drugs play an equally important role. Fears for cardiotoxicity should not discourage from using anthracyclines in many oncologic settings. Cardioprotective strategies are available and should be used more pragmatically in routine clinical practice.     

Dexrazoxane (ICRF-187)

• 1.Dexrazoxane (ICRF-187) is the only clinically approved drug for use in cancer patients to prevent anthracycline mediated cardiotoxicity.
• 2.The mode of action appears to be mainly due to the potential of the drug to remove iron from iron/anthracycline complexes and thus reduce free radical formation by these complexes.
• 3.Dexrazoxane also influences cell biology by its ability to inhibit topoisomerase II and its effects on the regulation of cellular iron homeostasis.
• 4.Although the cardioprotective effect of dexrazoxane in cancer patients undergoing chemotherapy with anthracyclines is well documented, the potential of this drug to modulate topoisomerase II activity and cellular iron metabolism may hold the key for future applications of dexrazoxane in cancer therapy, immunology, or infectious diseases.

     

Cardiac toxicity of antineoplastic anthracyclines

Anthracyclines play a major role in the treatment of solid malignancies, but their clinical use is limited by acute or chronic cardiac toxicity. This is not due to the same molecular action involved in the antineoplastic effect, i.e. topoisomerase II inhibition, but can be attributed to different mechanisms: free radical generation, stimulation of sarcoplasmic reticulum calcium release, binding to anionic phospholipids, alteration of sphingolipid metabolism, modulation of gene expression. Anthracycline metabolites, particularly 13-hydroxy derivatives, might contribute to impair iron and calcium homeostasis. Unresolved issues are the relative importance of such injurious mechanisms and the relationship between acute and chronic toxicity. Attempts to reduce anthracycline toxicity have been focused on the development of new derivatives, on the adoption of peculiar delivery systems, and on the association with substances able to interfere with the mechanism responsible for cardiotoxicity. Many anthracyclines have been synthesized and screened, but no major improvement in therapeutic index has been obtained. A possible exception might be represented by the new disaccharidic derivatives, which have provided promising results in preclinical studies. Liposome encapsulation and association with the iron chelator dexrazoxane have also proved to be useful. Novel approaches are targeted at the effects of anthracyclines on nitric monoxide metabolism and on sphingolipid metabolism.     

Anthracycline-induced cardiotoxicity

The anthracyclines constitute a group of drugs widely used for the treatment of a variety of human tumors. However, the development of irreversible cardiotoxicity has limited their use. Anthracycline-induced cardiotoxicity can persist for years with no clinical symptoms. However, its prognosis becomes poor after the development of overt heart failure, possibly even worse than ischemic or idiopathic dilated cardiomyopathies. Due to the successful action of anthracyclines as chemotherapic agents, several strategies have been tried to prevent/attenuate their side effects. Although anthracycline-induced injury appears to be multifactorial, a common denominator among most of the proposed mechanisms is cellular damage mediated by reactive oxygen species. However, it remains controversial as to whether antioxidants can prevent such side effects given that different mechanisms may be involved in acute versus chronic toxicity. The present review applies a multisided approach to the critical evaluation of various hypotheses proposed over the last decade on the role of oxidative stress in cardiotoxicity induced by doxorubicin, the most used anthracycline agent. The clinical diagnosis and treatment is also discussed.     

Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management

The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardio-toxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children. It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF. In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction. The beneficial effects of beta-adrenoceptor antagonists (beta-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.