What Is an Anthracycline?

Anthracyclines or anthracycline antibiotics are a class of chemotherapy drugs derived from Streptomyces peucetius var. Caesius.

Anthracyclines or anthracycline antibiotics are a class of chemotherapy drugs derived from Streptomyces peucetius var. Caesius.

Drug Name

Anthracyclines

Foreign name

Anthracyclines

Main indications

cancer

Anthracyclines I. Introduction

Anthracyclines, including doxorubicin, epirubicin, daunorubicin, and aclamycin, are widely used to treat hematological malignancies and solid tumors, such as acute leukemia, lymphoma, breast cancer, gastric cancer, Soft tissue sarcoma and ovarian cancer. Anthracyclines can be used in combination with other chemotherapeutic drugs and molecular targeted drugs. Combination therapy based on anthracyclines is usually the standard solution for first-line treatment. Anthracyclines have a broad antitumor spectrum, strong antitumor effect, and definite curative effects, which are indispensable, but can cause toxic side effects such as hair loss, bone marrow suppression and cardiotoxicity. Hematopoietic stimulating factors can be used for prevention and treatment of bone marrow suppression, and cardiotoxicity is the most serious side effect of anthracyclines ^[1] .

Anthracyclines 2. Mechanism

Anthracyclines have three main mechanisms of action:

By embedding between the bases of DNA double strands, a stable complex is formed, which inhibits DNA replication and RNA synthesis, thereby hindering the division of fast-growing cancer cells.

Inhibition of topoisomerase II, affecting the conversion of DNA supercoil to a relaxed state, thereby hindering DNA replication and transcription. Studies have shown that topoisomerase II inhibitors (in addition to anthracyclines also include etoposide, etc.) can prevent topoisomerase II from flipping, which is necessary for its detachment from its nucleic acid substrate. This means that topoisomerase II inhibitors make topoisomerase II complexes more stable after the DNA strand breaks, causing the latter to catalyze DNA destruction; at the same time, topoisomerase II inhibitors can also Hinders DNA repair by ligase.

Plutonium chelate iron ions to generate free radicals which destroy DNA, proteins and cell membrane structures.

Anthracyclines III. Commonly used anthracyclines

Daunorubicin

The first generation of anthracycline antitumor antibiotics for various types of acute leukemia (including granulocytic, lymphocytic and monocyte and granulo-monocyte), red leukemia, chronic myeloid leukemia, Malignant lymphoma can also be used for neuroblastoma, Ewing sarcoma, and nephroblastoma.

2. Doxorubicin (Doxorubicin)

Broad anti-tumor spectrum, suitable for acute leukemia (lymphocytic and granulocyte), malignant lymphoma, breast cancer, bronchial lung cancer (undifferentiated small cell and non-small cell), ovarian cancer, soft tissue sarcoma, osteogenic meat Tumor, rhabdomyosarcoma, Ewing sarcoma. Nephroblastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck squamous cell carcinoma, testicular cancer, gastric cancer, liver cancer, etc.

3.Arrubicin

Arubicin has excellent effects on acute leukemia, malignant lymphoma, gastric cancer, lung cancer, breast cancer, and ovarian cancer. It is also effective against doxorubicin and daunorubicin-resistant cases, and hair loss and stomatitis are all more effective. light.

In addition, there are epirubicin (epirubicin), idarubicin, penrubicin (only for the treatment of bladder cancer), mitoxantrone (a derivative of anthraquinones) and so on.

In addition, as an antibiotic, anthracyclines also have antibacterial activity, but due to their excessive toxicity, they have never been used to treat infections.

Anthracyclines

Anthracyclines have three main mechanisms of action:

1. By embedding between the bases of the DNA double strand, a stable complex is formed, which inhibits DNA replication and RNA synthesis, thereby hindering the division of fast-growing cancer cells.

2. Inhibition of topoisomerase II, affecting the transformation of DNA supercoil to a relaxed state, thereby hindering DNA replication and transcription. Studies have shown that topoisomerase II inhibitors (in addition to anthracyclines also include etoposide, etc.) can prevent topoisomerase II from flipping, which is necessary for its detachment from its nucleic acid substrate. This means that topoisomerase II inhibitors make topoisomerase II complexes more stable after the DNA strand breaks, causing the latter to catalyze DNA destruction; at the same time, topoisomerase II inhibitors can also Hinders DNA repair by ligase.

3. After chelating iron ions, free radicals are generated to destroy DNA, proteins and cell membrane structures.

Anthracyclines V. Cardiotoxicity and preventive measures

1. Clinical types of cardiotoxicity of anthracyclines

Anthracyclines can cause cardiac toxicity divided into early and late, the former includes acute, subacute and chronic.

1.1 Acute or subacute cardiotoxicity

Acute or subacute cardiotoxicity occurs during the anthracycline treatment or a few days to several weeks after the treatment, and has the following characteristics: (1) QRS wave low voltage, prolonged QT interval, non-specific ST-T segment Changes, etc .; (2) transient arrhythmia: sinus tachycardia is the most common, and various supraventricular, borderline, and ventricular arrhythmias can also occur; (3) various types of atrioventricular and bundle branch conduction resistance Stagnation. These electrophysiological changes rarely cause clinical symptoms, and subacute cardiotoxicity leads to acute left heart failure, pericarditis, or fatal pericarditis-myocarditis syndrome.

1.2 chronic cardiotoxicity

Chronic cardiotoxicity usually refers to heart damage that occurs within 1 year after the end of chemotherapy, and this type is the most common clinically. Its incidence is related to the total dose, peak level, and whether it is combined with other cardiotoxic antitumor drugs. It is characterized by congestive heart failure and / or cardiomyopathy. The clinical symptoms are mostly concealed and mostly irreversible. Relevant examinations show that the heart is enlarged, the left ventricular ejection fraction (LVEF) is reduced, and the ST-T segment changes, etc., which can rapidly progress to biventricular heart failure, and most often die within 8 weeks, with a mortality rate of 30% to 60%.

1.3 Advanced Cardiotoxicity

Advanced cardiotoxicity occurs 1 year after the end of chemotherapy, and mainly includes occult ventricular dysfunction, congestive heart failure, and arrhythmias. Cardiac toxicity in late onset is positively correlated with drug accumulation and medication frequency. Patients have no symptoms of impaired cardiac function in daily life, but stress conditions such as infection, surgery, pregnancy can increase the burden on the heart and induce symptoms.

2. Pathology

Cardiotoxicity caused by anthracyclines can lead to myocardial pathological changes, including many subcellular structures such as nucleoli, mitochondria, sarcoplasmic reticulum, lysosomes, and muscle fibers. With the increase of the total dose of anthracyclines, the degree of myocardial injury gradually increased, and it changed from reversible injury to irreversible injury. The main changes observed were: sarcoplasmic reticulum expansion and disappearance of muscle fibers. In the early stages of the disease, these changes occur in scattered myocardial cells. With the development of cardiac toxicity, the number of diseased cells gradually increases, and most of the myocardium is affected. In the advanced stage, scattered cardiomyocytes disappear and are replaced by fibrous tissue. Electron microscopy showed that the T-tube system and sarcoplasmic expansion and fusion, fibers lost actin and myosin, and mesenchymal cells and fibroproliferation. This pathological change is unique to anthracycline anticancer drugs and is distinct from viral cardiomyopathy or ischemic myocardial injury. This pathological change affects myocardial contractility, which leads to cardiac dysfunction.

3. Mechanism of occurrence

Oxidative stress theory, metabolite theory, calcium overload theory, immune response theory, etc.

3.1 Free radical damage theory

The mechanism of anthracycline anti-tumor drug cardiotoxicity is not very clear at present. Most of the previous researches believe that the damage of anthracyclines to myocardium is related to the formation of a large number of free radicals in the body. Anthraquinone groups in anthracyclines are reduced to semiquinone radicals by various reductase and NADH dehydrogenase enzyme systems, and then undergo a series of electron transfer processes to generate superoxide anions (O-2) And hydroxyl radicals (OH-). These free radicals can cause lipid peroxidation of mitochondria and microsomes, which can cause strong damage to various cells. Antioxidant enzymes such as Superoxide Dismutase (SOD) and Glutathione Peroxidase (GSH-Px) in normal myocardium are lower than other tissues, and anthracycline antitumor drugs can reduce The content of GSH-Px and SOD in the myocardium prevents the free radicals and superoxides produced by anthracycline antitumor drugs from being removed in time, which damages myocardial cells. In addition, anthracycline antitumor drugs can also

Radicals generate free radicals, which have a high affinity for Fe3 +, and produce anthracene-iron chelates. The chelates can transfer electrons from thiol compounds to oxygen molecules. Anthracycline-iron chelates have high affinity for cardiac phospholipids, and when combined with cardiolipin, they can cause damage to organelle membrane function and produce cardiotoxicity.

3.2 Calcium Overload and Energy Metabolism Disorders Ca2 + is mostly stored in mitochondria, sarcoplasmic reticulum, and sarcolemma. Ca2 + plays an important role in maintaining the excitation-contraction coupling of cardiomyocytes. Anthracyclines can activate Ca2 + channels on the sarcoplasmic network to increase the Ca2 + released from the sarcoplasmic network to the cytoplasm. The rapid increase of intracellular free Ca2 + concentration can affect ECG activity and cause various arrhythmias. This is calcium overload. Anthracyclines can also inhibit the Ca2 + -ATPase gene expression on the sarcoplasmic reticulum of cardiomyocytes, affect the biosynthesis of Ca2 + -ATPase, reduce its activity, reduce the ability of sarcoplasmic reticulum to take up Ca2 +, reduce mitochondrial production of ATP, and myocardium Impaired energy metabolism, aggravates cell damage, and even causes myocardial cell death.

3.3 The study of iron ion metabolism disorder found that another important mechanism of anthracycline cardiotoxicity may be the change of iron regulatory protein-iron effector binding. Under normal physiological conditions, there is only a very small amount of biologically active free iron in myocardial cells. Most of the iron ions are bound to ferritin and exist in the form of bound iron. Ferritin, as the main storage form of iron in cardiac muscle cells, can prevent the escape of iron ions and avoid damage to tissues and cells. Under pathological conditions, certain reducing agents can reduce ferritin, causing it to release active Fe2 +, which can participate in catalyzing the Haber-Weiss reaction to generate oxygen free radicals, which can have a toxic effect on the heart muscle.

Other theories: there are apoptosis theory, immune response theory, etc., but these theories have not been thoroughly studied.

4 preventive measures

4.1 Limiting cumulative dose

Limiting cumulative doses is one of the most important measures to prevent cardiotoxicity of anthracyclines. The cumulative dose of doxorubicin should be limited to 550mg · m, the cumulative dose of epirubicin should be less than 900mg · m, and no clear cumulative dose of anthracyclines such as daunorubicin and mitoxantrone has been recommended.

4.2 Changing the administration method

Clinical studies have found that slow intravenous doxorubicin (> 6h) can significantly reduce drug toxicity, but its antitumor effect may be affected.

4.3 Application of Liposome Anthracyclines

Currently used liposome anthracycline drugs include liposome daunorubicin, liposome doxorubicin, and polyethylene glycol-coated liposome doxorubicin. The application of these drugs not only improves the efficacy, but also Reduced toxic side effects. Among them, polyethylene glycol-coated liposomes doxorubicin has a longer drug half-life than the former two, and they have comparable efficacy, but the incidence of cardiac toxicity is lower.

4.4 Free radical scavenger

The most important mechanism of anthracycline-induced myocardial toxicity is that the generation of free radicals cannot be cleared in time, which causes myocardial damage. Therefore, if a radical scavenger is used, a protective effect can be achieved. For example, methylflavonolamine can significantly reduce the levels of serum creatine kinase and lactate dehydrogenase in anthracycline-induced myocardial injury mice, significantly increase the SOD activity in myocardial tissue, and enhance the function of oxygen free radical scavenging systems Thereby reducing the damage to the myocardium by oxygen free radicals.

4.5 Calcium Antagonist

The theory of calcium overload is another important mechanism of myocardial toxicity caused by anthracyclines, so calcium antagonists also have a protective effect on myocardium. For example, the calcium antagonist verapamil has been proven to be myocardial protective in a large number of clinical treatment studies, and it has an inhibitory effect on anthracycline-induced in vivo lipid peroxidation damage. Related studies have also confirmed that fructose 1,6-diphosphate can promote increased ATP synthesis, pump more calcium ions from the sarcoplasmic serous fluid into the sarcoplasmic reticulum or extracellular, thereby reducing the calcium concentration of cells. It can reduce the toxicity of adriamycin to the myocardium by reducing the free calcium in the myocardial cells and changing the activity.

4.6 Mitochondria Protective Agent

Anthracyclines can cause myocardial energy metabolism disorders, and mitochondria play a major role in energy metabolism, so the application of mitochondrial protective agents has also become one of the important measures to protect myocardium. Saffronic acid can significantly reduce the degree of mitochondrial DNA break and increase mitochondrial membrane potential, increase cytochrome C oxidase activity and its mRNA expression level of subunit II, significantly reduce the content of myocardial mitochondrial superoxide anion, and increase GSH-PX activity. It shows that saffron acid can significantly reduce myocardial mitochondrial damage in adriamycin. Some scholars in China have used ginkgo biloba tablets, diosgenin tablets and other drugs for research, and have also obtained the results of reduced myocardial damage.

4.7 Apoptosis inhibitor

Although the theory of anthracycline-induced apoptosis has not been studied in depth, and the role of apoptosis inhibitors is also controversial, more and more scholars believe that cells in the occurrence and development of cardiomyopathy caused by anthracyclines Apoptosis plays an important role. The study found that adiponectin can reduce myocardial apoptosis induced by doxorubicin by up-regulating the AMPK signaling pathway through in vivo and in vitro experiments.

4.8 Iron ion chelator

Iron ion chelating agents such as dextroimide and the like. Dexpropionimide is a 2-dioxopropylazine complex that hydrolyzes to form three EDTA analogs. The three hydrolysates can not only chelate with free iron ions, but also capture Fe3 + from Fe3 + -anthracycline chelates. , Thereby reducing the generation of oxygen free radicals, thereby inhibiting the cardiotoxicity of anthracyclines.

4.9 Antioxidants

A large number of studies have shown that some drugs with antioxidant effects (such as vitamin E, vitamin C, vitamin A, N-acetylcysteine, glutathione, ursolic acid, melatonin, etc.) do not have cardioprotective effects ideal. But for melatonin and vitamin E, Wahab et al. [30] hold different views. Their research shows that melatonin and vitamin E have obvious cardioprotective effects, especially melatonin is more significant, and both of them help improve the antitumor effect of anthracyclines. So whether the protective effect of melatonin is ideal remains to be further studied. Flavonoids (such as quercetin, monoHER, quercitrin, etc.) have iron chelation, antioxidant effects, and carbonyl reductase inhibitory effects, so they can reduce the cardiotoxicity of anthracyclines].

4.10 Chinese medicine

As for anthracycline-based myocardial injury protective agents, domestic scholars have also done a lot of research on traditional Chinese medicine. Traditional Chinese medicines, including ginkgo biloba extract (EGb761), astragalus, baicalin, silibinin, acanthopanax senticosus saponin, and Shengmai injection, can fight cardiotoxicity by regulating the balance of free radicals in the body. Pharmacological and clinical studies It shows that it can protect the cardiotoxicity caused by anthracyclines ^[2] .