Cardiotoxicity of Doxorubicin in Acute Leukemia

Abstract

Doxorubicin, an anthracycline chemotherapeutic agent, is widely utilized in the treatment of acute leukemia due to its potent anti-neoplastic properties. However, its clinical utility is limited by the occurrence of dose-dependent cardiotoxicity, which may manifest as cardiomyopathy, heart failure, or arrhythmias. This review provides an overview of the mechanisms underlying doxorubicin-induced cardiotoxicity, including oxidative stress, mitochondrial dysfunction, and DNA damage. Additionally, it discusses risk factors predisposing patients to cardiotoxicity, such as cumulative dose, age, pre-existing cardiac conditions, and concomitant use of other cardiotoxic agents. Furthermore, this review highlights various strategies for the prevention and management of doxorubicin-induced cardiotoxicity, including the use of cardioprotective agents, cardiac monitoring protocols, and lifestyle modifications. Finally, future directions for research aimed at minimizing cardiotoxicity while preserving the anti-neoplastic efficacy of doxorubicin in acute leukemia treatment are discussed.

Introduction

I. INTRODUCTION

Doxorubicin, a widely utilized anthracycline chemotherapeutic agent, is a cornerstone in the treatment of acute leukemia due to its potent anti-neoplastic properties. However, its clinical utility is tempered by the onset of dose-dependent cardiotoxicity, presenting a significant challenge in the management of patients undergoing chemotherapy. The mechanisms underlying doxorubicin-induced cardiotoxicity are multifactorial and complex.

II. LITERARY REVIEW AND METHODOLOGY

At the cellular level, doxorubicin generates reactive oxygen species (ROS) through redox cycling and iron-mediated reactions, leading to oxidative stress and subsequent damage to cellular components such as lipids, proteins, and DNA. Mitochondrial dysfunction is another hallmark of doxorubicin cardiotoxicity, characterized by impaired electron transport chain activity, ATP depletion, and mitochondrial membrane damage. Furthermore, doxorubicin interferes with calcium homeostasis, disrupting excitation-contraction coupling and contributing to myocardial contractile dysfunction. Additionally, the drug induces DNA damage through the formation of doxorubicin-DNA adducts and inhibition of topoisomerase II activity, triggering apoptotic pathways in cardiac myocytes. Although doxorubicin is an excellent tumoricidal agent, it is plagued by cardiotoxicity. Doxorubicin heavily concentrates in the nucleus but induces tubular and mitochondrial damage as well as nuclear alterations. Acute cardiac toxicity is primarily detected by dysrhythmias; chronic doxorubicin cardiomyopathy is characterized by congestive heart failure. Risk factors for developing cardiomyopathy include total cumulative dose of doxorubicin as well as radiation therapy, age of the patient and use of certain other chemotherapeutic agents [3]. 

Several risk factors predispose patients to heightened susceptibility to doxorubicin-induced cardiotoxicity. Cumulative dose is a significant determinant, with higher total doses correlating with increased incidence and severity of cardiac dysfunction. Advanced age, pre-existing cardiac conditions (e.g., hypertension, coronary artery disease), and concurrent administration of other cardiotoxic agents (e.g., trastuzumab) further augment the risk of cardiotoxicity.

Clinical manifestations of doxorubicin-induced cardiotoxicity vary widely, ranging from asymptomatic declines in left ventricular ejection fraction (LVEF) to symptomatic heart failure and life-threatening arrhythmias. Given the potential for irreversible cardiac damage, vigilant cardiac monitoring is imperative throughout the course of treatment. Echocardiography remains the cornerstone for assessing cardiac function, enabling the early detection of subclinical cardiac dysfunction and informing treatment decisions.

Prevention strategies aim to mitigate the risk of cardiotoxicity while optimizing therapeutic efficacy. Dexrazoxane, a cardioprotective agent, has shown promise in reducing doxorubicin-induced cardiotoxicity by chelating iron and scavenging ROS. Liposomal formulations of doxorubicin offer an alternative approach, with decreased cardiac uptake and enhanced tumor targeting. Lifestyle modifications, including regular exercise and dietary interventions, may also confer cardioprotective benefits.

III. DISCUSSION AND RESULTS

Cardiotoxicity of doxorubicin in acute leukemia refers to the adverse effects on the heart associated with the use of doxorubicin chemotherapy in the treatment of acute leukemia. Doxorubicin, a potent anticancer drug belonging to the anthracycline class, is highly effective in killing cancer cells, including those found in acute leukemia. However, one of the major drawbacks of doxorubicin therapy is its potential to cause damage to the heart muscle, leading to various cardiac complications.

The cardiotoxic effects of doxorubicin can manifest as:

1. Cardiomyopathy: Doxorubicin-induced cardiomyopathy refers to damage to the heart muscle, which can lead to a decrease in the heart's ability to pump blood effectively.
2. Heart Failure: Chronic exposure to doxorubicin can weaken the heart muscle over time, potentially resulting in heart failure, where the heart is unable to pump enough blood to meet the body's needs.
3. Arrhythmias: Doxorubicin can disrupt the normal electrical activity of the heart, leading to abnormal heart rhythms or arrhythmias, which can be life-threatening in severe cases.

The exact mechanisms underlying doxorubicin-induced cardiotoxicity are complex and not fully understood but may involve oxidative stress, mitochondrial dysfunction, and DNA damage within the heart muscle cells.

Patients receiving doxorubicin therapy for acute leukemia are typically monitored closely for signs of cardiotoxicity, and efforts are made to minimize the risk through careful dosing and the use of cardioprotective agents when appropriate. However, despite these precautions, cardiotoxicity remains a significant concern in the management of acute leukemia patients receiving doxorubicin treatment. Therefore, ongoing research is focused on developing strategies to mitigate cardiotoxicity while maintaining the efficacy of doxorubicin in treating leukemia.

In cases where cardiotoxicity ensues, prompt intervention is paramount. Dose adjustments and treatment with heart failure medications, such as angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, can help mitigate symptoms and preserve cardiac function. Cardiac rehabilitation programs offer comprehensive support, encompassing exercise training, risk factor modification, and psychosocial counseling.

Cardiomyopathy induced by doxorubicin (DOX) is considered an extremely serious adverse effect of oncologic treatment. It is known that this disease significantly affects the quality of patients’ life who survived cancer, especially children. Since its discovery, several molecular mechanisms have been proposed to understand the pathogenesis of acute and chronic DOX-induced cardiotoxicity (DIC), including oxidative stress, iron metabolism, Ca2+ homeostasis dysregulation, sarcomeric structure alterations, gene expression modulation, and apoptosis. Based on these mechanisms, different strategies have been developed in order to protect the heart during cancer treatment, including the administration of iron-chelating antioxidants and adrenergic receptor agonists. However, the use of these drugs is limited due to their adverse side effects as well as the loss of beneficial cardiac effects years after the end of the treatment [6]. 

Looking ahead, future research endeavors aim to refine risk stratification algorithms, elucidate novel therapeutic targets, and develop targeted drug delivery systems to minimize cardiotoxicity while preserving the anti-neoplastic efficacy of doxorubicin in the treatment of acute leukemia. By advancing our understanding of doxorubicin-induced cardiotoxicity, we can optimize treatment outcomes and enhance the quality of life for leukemia patients undergoing chemotherapy.

In conclusion, the cardiotoxicity of doxorubicin represents a significant clinical concern in the management of acute leukemia. While its anti-neoplastic efficacy is indisputable, the potential for cardiac damage underscores the importance of a multifaceted approach to treatment optimization. Understanding the intricate mechanisms underlying doxorubicin-induced cardiotoxicity is essential for developing targeted preventive and therapeutic strategies.

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Copyright

Copyright © 2024 Amerova Dilafruz Abdikhalimovna, Safarova Farangiz Khasanovna. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.