Cardiotoxicity in childhood cancer survivors: strategies for prevention and management.
ABSTRACT 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.
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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.Toxicology and Applied Pharmacology 11/2013; 274(1). DOI:10.1016/j.taap.2013.10.023 · 3.63 Impact Factor
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ABSTRACT: Hepatoblastoma is the most common liver malignancy in children, typically diagnosed before age 2. The survival rate for hepatoblastoma has increased dramatically in the last 30 years, but the typical chemotherapeutic agents used for treatment are associated with significant toxicity. In this report, the authors present two cases of hepatoblastoma treated with surgical resection and a novel biotherapeutic regimen that included opioid growth factor (OGF). Case #1 is an infant diagnosed with a large mass on prenatal ultrasound. After subsequent diagnosis of hepatoblastoma, she was treated with one course of neoadjuvant chemotherapy at approximately 1 week of age. Following significant complications from the chemotherapy (neutropenic fever, pneumonia and sepsis), the patient's parents declined further chemotherapy, and the infant was treated with surgical resection and opioid growth factor (OGF)/low dose naltrexone (LDN). She is currently at close to 10 years disease-free survival. Case #2 is a child diagnosed with a liver mass on ultrasound at 20 months of age, later biopsy-proven to represent hepatoblastoma. Due to existing co-morbidities including autosomal recessive polycystic kidney disease and hypertension, and indications from the biopsy that the tumor might be insensitive to chemotherapy, the parents elected not to proceed with neoadjuvant chemotherapy. The patient was treated with surgical resection and OGF/LDN, and is currently at more than 5 years disease-free survival. This case series highlights the need for less toxic treatment options than conventional chemotherapy. Modulation of the OGF-OGF receptor axis represents a promising safe and therapeutic avenue for effective treatment of hepatoblastoma.Investigational New Drugs 12/2012; DOI:10.1007/s10637-012-9918-3 · 2.93 Impact Factor
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ABSTRACT: BACKGROUND: Reports on incidence and factors associated with anthracycline cardiotoxicity in patients with Ewing sarcoma vary and few studies evaluate effect over time. Longitudinal trends in cardiac function and prognostic value of % decline in ejection fraction (EF) during therapy have not been previously described in Ewing sarcoma. PROCEDURE: A retrospective review of patients age <17 years, diagnosed with Ewing sarcoma during 1978-2006, treated at British Columbia Children's Hospital with anthracycline chemotherapy was undertaken. Echocardiograms performed pre-treatment, worst function during treatment, on therapy completion; worst function during surveillance and the most recent echocardiogram were reviewed. Cardiac toxicity was graded using Common Terminology Criteria for Adverse Events v 3.0 and 4.0. RESULTS: Among 71 eligible patients, median age at diagnosis 11.1 years, median cumulative dose of anthracycline was 365 mg/m(2) . There were 397 echocardiograms with 153 (39%) abnormal. There were 21/71 patients with EF < 50%, 11 with EF < 40% and five cardiac deaths including 2/3 patients post-cardiac transplant. The median time to worst cardiac function was 51 months. Post-therapy completion 16/71 patients with progressive decline in cardiac function were noted. No patient with 10-15% decline in EF during therapy developed cardiotoxicity. Younger age (P = 0.004) and low BMI (P = 0.034) as continuous variables with anthracycline administration by IV push (P = 0.03) were risk factors for cardiotoxicity on univariate analysis but not significant within logistic regression models. CONCLUSIONS: The high incidence of cardiotoxicity associated with higher administered anthracycline dose, young age, bolus infusion, and EF decline warrants evaluation in a larger cohort. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.Pediatric Blood & Cancer 05/2013; 60(5). DOI:10.1002/pbc.24404 · 2.56 Impact Factor