Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

Choi, Hyoung Soo; Park, Eun Sil; Kang, Hyoung Jin; Shin, Hee Young; Noh, Chung Il; Yun, Yong Soo; Ahn, Hyo Seop; Choi, Jung Yun

doi:10.3346/jkms.2010.25.9.1336

Cited by 43 publications

(32 citation statements)

References 29 publications

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“…The effect was greater in girls than in boys (153). Protection from anthracycline cardiotoxicity was also documented in pediatric patients with solid tumors (28,62). Cardioprotection was accomplished in the presence of sustained anticancer activity by the combination.…”

Section: Iron Chelators As Cardioprotective Agentsmentioning

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 Chelators As Cardioprotective Agentsmentioning

confidence: 99%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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“…Sometimes DEX is incorporated with anthracyclines as a potential cardioprotective agent during cancer treatment (Wouters et al, 2005;Choi et al, 2010). Therefore, another set of metabolic assays was performed with the addition of DEX to determine whether it significantly altered the metabolic conversion of anthracyclines to their major metabolites.…”

Section: Chemicals and Enzymesmentioning

confidence: 99%

A Correlation between Cytotoxicity and Reductase-Mediated Metabolism in Cell Lines Treated with Doxorubicin and Daunorubicin

Bains

Szeitz

Lubieniecka

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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The role of metabolism in daunorubicin (DAUN)-and doxorubicin (DOX)-associated toxicity in cancer patients is dependent on whether the parent drugs or major metabolites, doxorubicinol (DOXol) and daunorubicinol (DAUNol), are the more toxic species. Therefore, we examined whether an association exists between cytotoxicity and the metabolism of these drugs in cell lines from nine different tissues. Cytotoxicity studies using MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] cell viability assays revealed that four cell lines [HepG2 (liver), HCT-15 (colon), NCI-H460 (lung), and A-498 (kidney)] were more tolerant to DAUN and DOX than the five remaining cell lines [H9c2 (heart), PC-3 (prostate), OVCAR-4 (ovary), PANC-1 (pancreas), and MCF-7 (breast)], based on significantly higher LC 50 values at incubation times of 6, 24, and 48 hours. Each cell line was also assessed for its efficiency at metabolizing DAUN and DOX. The four drug-tolerant cell lines converted DAUN/DOX to DAUNol/DOXol more rapidly than the five drug-sensitive cell lines. We also determined whether exposure to DAUN or DOX induced an increase in metabolic activity among any of these nine different cell types. All nine cell types showed a significant increase in their ability to metabolize DAUN or DOX in response to pre-exposure to the drug. Western blot analyses demonstrated that the increased metabolic activity toward DAUN and DOX correlated with a greater abundance of eight aldo-keto and two carbonyl reductases following exposure to either drug. Overall, our findings indicate an inverse relationship between cytotoxicity and DAUN or DOX metabolism in these nine cell lines.

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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).…”

mentioning

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 for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

Cited by 43 publications

References 29 publications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

A Correlation between Cytotoxicity and Reductase-Mediated Metabolism in Cell Lines Treated with Doxorubicin and Daunorubicin

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

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