Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.
"The molecular and genetic mechanisms of anthracycline-related cardiotoxicity are not completely understood, but the generation of iron-dependent, reactive free radicals that induce lipid peroxidation with consequent membrane damage is plausible . Other possible contributory mechanisms include direct effects on topoisomerase (mediated through topoisomerase 2β)  , decreased activity of Na + , K + -ATPase, mitochondrial damage, DNA damage, derangement of the calcium current with the inhibition of the sarcoplasmic reticulum, accumulation of tumor suppressor protein, and mitochondrial apoptosis in the heart and cardiomyocytes   . "
[Show abstract][Hide abstract] ABSTRACT: Advances in treating childhood cancers over the past 40 years have more than doubled 5-year survival rates. More effective use of chemotherapeutic agents has been key to this success. However, the increase has come at a price: chronic conditions are significantly more prevalent in long-term survivors of childhood cancer than they are in the general population, and managing these survivors can be challenging. In patients receiving anthracyclines, cardiotoxicity is the leading cause of morbidity and mortality after relapse and second malignancies. More than 50% of patients exposed to anthracyclines exhibit some form of cardiac dysfunction within 20 years after completing chemotherapy, and about 5% develop heart failure. These conditions greatly reduce the quality of life of the individual and also consume substantial amounts of healthcare resources. Dexrazoxane has been used to reduce anthracycline-related cardiotoxicity in children with cancer, but in 2011, the European Medicines Agency determined, on what it acknowledged were limited data, that dexrazoxane was contraindicated in children. Here, we review the evidence for the clinical effects of dexrazoxane in children. Studies published since 2011 have confirmed the efficacy of dexrazoxane in preventing or reducing anthracycline-related cardiotoxicity in children with cancer, and no new evidence of increased risks for recurrence of primary or second malignancies, or reductions in antitumor efficacy has been reported. As a result, we believe that dexrazoxane should be available to children with high-risk cancers to reduce the risk of cardiotoxicity associated with high-dose anthracycline treatment.
Progress in Pediatric Cardiology 09/2014; 36(1-2). DOI:10.1016/j.ppedcard.2014.09.007
"The known risk factors for anthracycline-induced cardiotoxicity include cumulative dose, female gender, higher dose rate, cranial irradiation and age. Similar to cisplatin, anthracyclines are associated with a markedly higher risk of toxicity in young children vs. adults (Harake et al., 2012; de Ville de Goyet et al., 2012). Anthracycline-induced cardiotoxicity is associated with significant morbidity and an appreciable mortality rate. "
[Show abstract][Hide abstract] ABSTRACT: Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children.
Frontiers in Genetics 04/2014; 5:78. DOI:10.3389/fgene.2014.00078
"This effect, which manifests in patients receiving a cumulative dose in excess of 550 mg/m 2 DOX (~15–22 mg/kg, depending on body size (Freireich et al., 1966)), may occur shortly after drug therapy or several years later and often leads to dilated cardiomyopathy (CM) and life-threatening congestive heart failure (CHF) (Lipshultz et al., 1991; Mettler et al., 1977; Sorensen et al., 1997; Von Hoff et al., 1979). The 2-year survival rate for these patients is less than 50% and for 10% of those affected, heart transplant is the only survival option (Harake et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Doxorubicin (DOX) is a widely prescribed treatment for a broad scope of cancers, but clinical utility is limited by the cumulative, dose-dependent cardiomyopathy that occurs with repeated administration. DOX-induced cardiotoxicity is associated with the production of reactive oxygen species (ROS) and oxidation of lipids, DNA and proteins. A major cellular defense mechanism against such oxidative stress is activation of the Keap1/Nrf2-antioxidant response element (ARE) signaling pathway, which transcriptionally regulates expression of antioxidant genes such as Nqo1 and Gstp1. In the present study, we address the hypothesis that an initial event associated with DOX-induced oxidative stress is activation of the Keap1/Nrf2-dependent expression of antioxidant genes and that this is regulated through drug-induced changes in redox status of the Keap1 protein. Incubation of H9c2 rat cardiac myoblasts with DOX resulted in a time- and dose-dependent decrease in non-protein sulfhydryl groups. Associated with this was a near 2-fold increase in Nrf2 protein content and enhanced transcription of several of the Nrf2-regulated down-stream genes, including Gstp1, Ugt1a1, and Nqo1; the expression of Nfe2l2 (Nrf2) itself was unaltered. Furthermore, both the redox status and the total amount of Keap1 protein were significantly decreased by DOX, with the loss of Keap1 being due to both inhibited gene expression and increased autophagic, but not proteasomal, degradation. These findings identify the Keap1/Nrf2 pathway as a potentially important initial response to acute DOX-induced oxidative injury, with the primary regulatory events being the oxidation and autophagic degradation of the redox sensor Keap1 protein.
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