Subacute cardiotoxicity caused by anthracycline therapy in children: can dexrazoxane prevent this effect?

Kovàcs, Gabór; Erlaky, Hajna; Tóth, Kornélia; Horvath, Erzsebet; Szabolcs, Judit; Csóka, Monika; Jókúti, László; Erdélyi, Dániel; Müller, Judit

doi:10.1007/s00431-006-0370-2

Cited by 9 publications

(6 citation statements)

References 5 publications

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“…According to data from in vitro studies, the damaging effects of reactive oxygen species (ROS), generated by the interaction of doxorubicin with iron, plays a critical role in the pathogenesis of the chronic cardiotoxicity (66,237). Sub-acute and sub-chronic toxicities are uncommon (133).…”

Section: Iron Chelation In Cancermentioning

confidence: 99%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2a). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2a inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 18, 930-955.

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Section: Iron Chelation In Cancermentioning

confidence: 99%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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“…DEX was shown to reduce the mitochondria toxicity of DOX in adult rats in vivo and rat cardiomyocytes in vitro (17,29). DEX has reduced or prevented DOX-induced reductions in fractional shortening (FS) and left ventricle (LV) ejection fraction in children (6,25,53,64). A recent study (32) identified greater DOX toxicity and greater benefit from DEX protection in female children (32).…”

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confidence: 99%

Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training

Calvé¹,

Haddad²,

Barama³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Calvé A, Haddad R, Barama SN, Meilleur M, Sebag IA, Chalifour LE. Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training. Am J Physiol Heart Circ Physiol 302: H2048 -H2057, 2012. First published March 23, 2012; doi:10.1152/ajpheart.01069.2011The impact of cancer therapies on adult cardiac function is becoming a concern as more children survive their initial cancer. Cardiovascular disease is now a significant problem to adult survivors of childhood cancer. Specifically, doxorubicin (DOX) may be particularly harmful in young girls. The objective of this study was to characterize DOX damage and determine the ability of dexrazoxane (DEX) to reduce DOX-mediated cardiac damage in sedentary and swim-trained female rats. Female Sprague-Dawley rats were left intact or ovariectomized (OVX) at weaning then injected with DEX (60 mg/kg) before DOX (3 mg/kg), DOX alone, or PBS. Rats were separated into sedentary and swim cohorts. Body weight was reduced in DOX:DEX-but not PBSor DOX-treated rats. Echocardiographic parameters were similar in sedentary rats. Swim training revealed greater concentric remodeling in DOX-treated rats and reduced fractional shortening in DOX:DEXtreated rats. Calsequestrin 2 was reduced with DOX and increased with DOX:DEX postswim. Sarco(endo)plasmic reticulum Ca 2ϩ -ATPase 2a was reduced and calsequestrin 2 reduced further by swim training only in intact rats. OVX rats were heavier and developed eccentric remodeling post-swim with DOX and eccentric hypertrophy with DOX:DEX. Changes in SERCA2a and calsequestrin 2 expression were not observed. Ovariectomized DOX-and DOX:DEXtreated rats stopped growing during swim training. DEX coinjection did not relieve DOX-mediated cardiotoxicity in intact or hormonedeficient rats. DOX-mediated reductions in growth, cardiac function, and expression of calcium homeostasis proteins were exacerbated by swim. DEX coadministration did not substantially relieve DOXmediated cardiotoxicity in young female rats. Ovarian hormones reduce DOX-induced cardiotoxicity.echocardiography; Sprague-Dawley rat; ovariectomy; sarco(endo) plasmic reticulum Ca 2ϩ -ATPase 2a; calsequestrin 2IT IS WELL RECOGNIZED THAT increasing numbers of children now survive childhood cancer because of treatment improvements. However, almost two-thirds of childhood cancer survivors have at least one chronic illness and close to one-third had severe or life-threatening conditions when only in their midtwenties (9, 44, 61). In addition, exercise testing of childhood cancer survivors has demonstrated a below-predicted exercise capacity (22, 63). The risk for cardiovascular disease was found to be high and was attributed to anthracycline treatment years earlier (2,27,49,54,65). Anthracycline use, mostly doxorubicin (DOX), daunorubicin, and epirubicin, remains common, and it is estimated that about one-half of childhood cancer survivors will have received anthracyclines. Evidence suggests that young females may have a greater incidence of DOX...

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“…Dexrazoxane has not yet been introduced as a standard prophylaxis of cardiotoxicity in children because there is insufficient evidence to make a recommendation for the use of dexrazoxane in the treatment of pediatric malignancies (10, 12). The short-to-medium-term efficacy of dexrazoxane in preventing doxorubicin-induced cardiotoxicity was investigated in two randomized trials (5, 13) and several smaller, nonrandomized, controlled trials (9, 21, 22), including one studying different malignancies in children.…”

Section: Discussionmentioning

confidence: 99%

Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

et al. 2010

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This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8±83.4 mg/m2 in the dexrazoxane group and 266.1±75.0 mg/m2 in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.

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Subacute cardiotoxicity caused by anthracycline therapy in children: can dexrazoxane prevent this effect?

Cited by 9 publications

References 5 publications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training

Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

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