Pediatric Anthracycline‐Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem‐Cell Modeling

Tripaydonis, Anne; Conyers, Rachel; Elliott, David A.

doi:10.1002/cpt.1311

Cited by 36 publications

(46 citation statements)

References 60 publications

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“…In an attempt to validate these associations in the setting of early onset severe ACT, our study identified that 14 out of 15 patients had at least one of the missense variants associated with cardiotoxicity to date. Nevertheless, incorporating these genetic markers into practice requires replication studies and further functional validation [41]. Importantly, both the onset of cardiotoxicity after anthracycline treatment and the dose at which cardiotoxicity was observed did not correlate with the burden of variants within this cohort.…”

Section: Discussionmentioning

confidence: 91%

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy

et al. 2020

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Background: Anthracyclines are a mainstay of chemotherapy. However, a relatively frequent adverse outcome of anthracycline treatment is cardiomyopathy. Multiple genetic studies have begun to dissect the complex genetics underlying cardiac sensitivity to the anthracycline drug class. A number of single nucleotide polymorphisms (SNPs) have been identified to be in linkage disequilibrium with anthracycline induced cardiotoxicity in paediatric populations. Methods: Here we screened for the presence of SNPs resulting in a missense coding change in a cohort of children with early onset chemotherapy related cardiomyopathy. The SNP identity was evaluated by Sanger sequencing of PCR amplicons from genomic DNA of patients with anthracycline related cardiac dysfunction. Results: All of the published SNPs were observed within our patient group. There was no correlation between the number of missense variants an individual carried with severity of disease. Furthermore, the time to cardiac disease onset post-treatment was not greater in those individuals carrying a high load of SNPs resulting from missense variants. Conclusions: We conclude that previously identified missense SNPs are present within a paediatric cohort with early onset heart damage induced by anthracyclines. However, these SNPs require further replication cohorts and functional validation before being deployed to assess anthracycline cardiotoxicity risk in the clinic.

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Section: Discussionmentioning

confidence: 91%

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy

et al. 2020

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“…More novel AC molecules such as Epirubicin and idarubicin and the structurally related molecule mitoxantrone have been proposed as less cardiotoxic variants of DOX. However, over the years, all types of AC have been shown to cause AC-induced cardiac toxicity [ 23 ].…”

Section: Chemotherapy-induced Cardiotoxicitymentioning

confidence: 99%

“…These genes play roles in DNA damage pathways, oxidative stress response, iron metabolism, drug transport, and sarcomere function. Mostly, the ABCC, CBR3, and SLC28A3 genes have emerged in the majority of studies cited, emphasizing their important role in the development of AC-related heart disease [ 23 ].…”

Section: Chemotherapy-induced Cardiotoxicitymentioning

confidence: 99%

Cardiotoxicity: A Major Setback in Childhood Leukemia Treatment

et al. 2021

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Ongoing research in the field of pediatric oncology has led to an increased number of childhood cancer survivors reaching adulthood. Therefore, ensuring a good quality of life for these patients has become a rising priority. Considering this, the following review focuses on summarizing the most recent research in anthracycline-induced cardiac toxicity in children treated for leukemia. For pediatric cancers, anthracyclines are one of the most used anticancer drugs, with over half of the childhood cancer survivors believed to have been exposed to them. Anthracyclines cause irreversible cardiomyocyte loss, leading to chronic, progressive heart failure. The risk of developing cardiotoxicity has been known to increase with the treatment-free interval and total cumulative dose. However, because of individual variations in anthracycline metabolism, it has recently been shown that there is no risk-free dose. Moreover, studies have shown that diagnosing anthracycline-induced cardiomyopathy in the symptomatic phase is associated with poor treatment response and prognosis. Thus, early and systematic evaluation of these patients is crucial to allow optimal therapeutic intervention. Although currently echocardiographic assessment of left ventricle ejection fraction and cardiac biomarker evaluation are being used for cardiac function monitoring in oncologic patients, there is no established follow-up and treatment protocol for these patients, and these methods are neither specific nor sensitive for identifying early cardiac dysfunction. All things considered, the need for ongoing research in the field of pediatric cardiooncology is crucial to offer these patients a chance at a good quality of life as adults.

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“…Unveiling the genetic variants that contribute to AIC is of upmost importance since it may give the clinicians the opportunity to identify patients at risk prior the treatment, and potentially modify the therapeutic regimens by using alternative drugs or cardioprotective agents. Early candidate gene association studies (CGAS) and genomewide association studies (GWAS) have started to reveal the first genes, that are primarily related to drug metabolism and transport, iron metabolism, DNA repair, oxidative stress, and calcium homeostasis, with no genes being directly linked to mitochondrial function regulation (123,124). However, given the small sample sizes of these studies, additional work is warranted to conclusively validate these variants and to discover new genes implicated in AIC susceptibility.…”

Section: Future Perspectivesmentioning

confidence: 99%

Mechanisms of Anthracycline-Induced Cardiotoxicity: Is Mitochondrial Dysfunction the Answer?

Murabito

Hirsch

Ghigo

2020

Front. Cardiovasc. Med.

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Cardiac side effects are a major drawback of anticancer therapies, often requiring the use of low and less effective doses or even discontinuation of the drug. Among all the drugs known to cause severe cardiotoxicity are anthracyclines that, though being the oldest chemotherapeutic drugs, are still a mainstay in the treatment of solid and hematological tumors. The recent expansion of the field of Cardio-Oncology, a branch of cardiology dealing with prevention or treatment of heart complications due to cancer treatment, has greatly improved our knowledge of the molecular mechanisms behind anthracycline-induced cardiotoxicity (AIC). Despite excessive generation of reactive oxygen species was originally believed to be the main cause of AIC, recent evidence points to the involvement of a plethora of different mechanisms that, interestingly, mainly converge on deregulation of mitochondrial function. In this review, we will describe how anthracyclines affect cardiac mitochondria and how these organelles contribute to AIC. Furthermore, we will discuss how drugs specifically targeting mitochondrial dysfunction and/or mitochondria-targeted drugs could be therapeutically exploited to treat AIC.

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Pediatric Anthracycline‐Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem‐Cell Modeling

Cited by 36 publications

References 60 publications

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy

Cardiotoxicity: A Major Setback in Childhood Leukemia Treatment

Mechanisms of Anthracycline-Induced Cardiotoxicity: Is Mitochondrial Dysfunction the Answer?

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