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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Ms Raffaella Greco
Dr. Eugenio Greco,
Anthracycline antibiotics are highly effective antineoplastic drugs used in a wide range of cancers, however they can have adverse effects on the heart. Depending on the needed dosage and presence of certain gene variants that may influence risk, use of cardiotoxic analogs, ACE-inhibitors and cardioprotective drugs may help to individualise treatment to prevent cardiotoxic risk.
Anthracycline use may, years after treatment, cause cardiomyopathy where the heart does not pump efficiently and congestive heart failure may ensue. Potentially irreversible dilated cardiomyopathy may occur (1). In animal models of anthracycline cardiotoxicity, irreversible mitochondrial impairment, in part related to free-radical injury during therapy, resulting in late cardiomyopathy was found. Long-term survivors of chidhood cancer have a greater than 8-fold increased risk of CV mortality compared to a healthy population 25 years after therapy. This risk increases progressively over time and appears related in part to anthracycline chemotherapy. Anthracycline-induced cardiotoxicity in long-term survivors of childhood cancer is characterised by reduced left ventricular wall thickness and mass, which is indicative of decreased cardiac muscle and depressed left ventricular contractility, signs of an unhealthy heart muscle (2). The cardiotoxic risk increases with the high cumulative anthracycline doses, anthracycline dose intensity, and radiotherapy, which, in patients with cancer treated with anthracyclines, can exacerbate anthracycline-induced cardiac tissue damage.
While some patients with little exposure have considerable cardiac damage others with higher exposure don't develop heart problems. Inter-individual variability in tolerance to (and efficacy of) cumulative anthracycline exposure has indicated a role for genetic susceptibility with this drug. It has been hypothesised that variations in genes with a function in doxorubicin pharmacology, (an anthracycline) may contribute to variation in doxorubicin toxicity (3). Evidence suggests that genetic variants affect the expression of proteins associated with the transport, metabolism and mechanism of action of doxorubicin, and may influence efficacy and toxicity (4). For example, single nucleotide polymorphisms (SNPs) in the ABCB1 transporter gene have been shown to influence both pharmacokinetics and outcome following doxorubicin chemotherapy. Similar associations have been described for SNPs in the carbonyl reductase (CRB1 and CRB3) genes: variants in the CBR1 and CBR3 genes are known to affect the enzyme's activity, and it has been hypothesised that cardiotoxic risk is increased among those who received low doses of anthracyclines if they carry these particular genetic variants (5). CBRs are enzymes that help metabolise anthracyclines into highly cardiotoxic C-13 alcohol metabolites (doxorubicin and daunorubicin into the cardiotoxic metabolites doxorubicinol and daunorubicinol), which are substances that can damage the heart: the CBR1 gene variant increased the risk of heart problems by more than five-fold, and the CBR3 gene variant increased the risk by more than three-fold. Multivariate analysis adjusted for age at diagnosis, gender, radiation to the heart, race/ethnicity, years of diagnosis, primary diagnosis, and follow-up showed that compared with with no anthracycline exposure, the risk of cardiomyopathy in those exposed to anthracyclines was: 2.02-fold higher at 1 to 100 mg/m2; 3.56-fold at 101 to 200 mg/m2; 11.43-fold at 201 to 300 mg/m2; 22.32-fold at 301 mg/m2 and higher. Patients with acute lymphoblastic leukaemia or non-Hodgkin's lymphoma are typically given lower doses of anthracyclines. However those with bone tumours, sarcomas, and acute myeloid leukaemia typically receive higher doses of anthracyclines, and therefore face an increased risk of cardiomyopathy regardless of gene status (6).
Patients who are found to have this specific gene variant could be offered an alternative noncardiotoxic chemotherapy or, if anthracyclines were still considered necessary, may benefit from aggressive surveillance and/or cardioprotection with cardioprotective agents. This would be an example of personalised medicine and an important step toward safer treatment of cancer patients (7). Attempts to reduce anthracycline cardiotoxicity have been directed towards:
Significant inter-individual variability in tolerance to cumulative anthracycline exposure has indicated a role for genetic susceptibility. A large number of genetic polymorphisms have been reported in the genes that mediate the metabolism, transport and pharmacological activity of doxorubicin. The clinical significance of these findings is still undergoing evaluation, but it has been hypothesised that a personalised treatment of cancer may be needed. Author's disclosures: None declared.
1.Exposure to anthracyclines during childhood causes cardiac injury. Lipshultz SE. Semin Oncol. 2006 Jun;33(3 Suppl 8):S8-14. 2.Comparison of left ventricular function by echocardiogram in patients with Wilms' tumor treated with anthracyclines versus those not so treated. Iarussi D, Indolfi P, Pisacane C, et al. Am J Cardiol. 2003 Aug 1;92(3):359-61. 3.Genotyping the risk of anthracycline-induced cardiotoxicity. Deng S, Wojnowski L. Cardiovasc Toxicol. 2007;7(2):129-34. 4.Gene variants predict anthracycline cardiotoxicity in young patients. Laino C. Oncology Times UK: July 2010 - Volume 7 - Issue 7 - p 10. 5. Pharmacogenetics of genes across the doxorubicin pathway Jamieson D, Boddy AV. Expert Opin Drug Metab Toxicol. 2011 Oct;7(10):1201-10. 6.Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes. A Children's Oncology Group study. 2010 ASCO Annual Meeting. J Clin Oncol 28:15s, 2010 (suppl; abstr 9512). 7.Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management. Iarussi D, Indolfi P, Casale F, et al. Paediatr Drugs. 2005;7(2):67-76. 8.Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors. Silber JH, Cnaan A, Clark BJ, et al. Am Heart J 2001;142(4):577-585. 9.Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lipshultz SE, Scully RE, Lipsitz SR, et al. Lancet Oncol. 2010 Oct;11(10):950-61. Epub 2010 Sep 16. 10.Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). Gonzalez-Covarrubias V, Kalabus JL, Blanco JG. Pharm Res. 2008 Jul;25(7):1730-4. Epub 2008 May 1.
Authors:1§Eugenio Greco – 2Raffaella Greco1ASP N° 1 - Cosenza - ITALY. § FESC
2Hematology and BMT Unit - Scientific Institute Ospedale San Raffaele - Milan – ITALY
Correspondence to: Eugenio Greco, MD, PhD, FESC http://eugenio.greco.docvadis.it http://www.medicitalia.it/grecoeugenio
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