Anthracyclines are a group of compounds isolated from bacteria that are used as cytostatic agents. Indications for the resulting agents, mitoxantrone, epirubicin, idarubicin, and daunorubicin, are leukemias and other carcinogenic diseases. Via processes of intercalation, the drugs target tumor cells and prevent their division.
What are anthracyclines?
Anthracyclines are a group of antibiotically active compounds. The compounds have been isolated from the bacterial genus Streptomyces and serve as cytostatic agents in chemotherapy. Specifically, the species Streptomyces coeruleorubidus and Streptomyces peuceticus snythetize the active compounds. The mechanisms of action of the isolated drugs are diverse. In particular, the active substances are directed against cells with a high division rate. All representatives of the anthracycline group are aromatic hydrocarbon molecules. These are cyclic and planar hydrocarbons with an aromatic system. Anthracyclines are also called anthracycline antibiotics. In addition to idarubicin, daunorubicin, and doxorubicin, the best-known representatives of this group of agents include mitoxantrone and epirubicin.
Pharmacologic action
One of the major mechanisms of action of anthracyclines is intercalation. This is known as the reversible intercalation of individual ions, atoms, or molecules into chemical compounds. The molecular structure of the intercalating particles hardly changes as a result of the intercalation. Inorganic chemistry speaks of intercalation when a wide variety of atoms, ions and smaller molecules are intercalated between the crystal lattice planes of the layered crystals, for example, when alkali metals are intercalated in graphite crystal lattices. The biochemical definition of the term is based on this definition of inorganic chemistry. With respect to DNA, we speak of processes of intercalation whenever single molecules enter the double helix DNA strand between adjacent base pairs. Such intercalation interferes with the replication as well as transcription of DNA. During the replication process, framing mutations occur. For this reason, intercalation is thought to have a mutagenic effect. Intercalation also disrupts protein biosynthesis processes. For the affected cells, this means cell death. In addition, anthracyclines carry the enzyme topoisomerase II. This enzyme loosens the helix turns of double-stranded DNA strands and thus alters the spatial structure of the DNA double helix. In biochemical terms, topoisomerase II temporarily cleaves both strands of DNA, consuming ATP. The resulting gap between the strands is used as a guide hole and accommodates another section of the double helix. Beyond intercalation and enzyme binding, anthracyclines are capable of free radical formation. Thus, they create double-strand breaks within tumor DNA. Their active ingredients also increase the permeability of the tumor cell membrane and kill the cells in this way.
Medical application and use
All anthracyclines target the proliferation or spread of malignant space-occupying tumors in different ways. Malignant tumors invasively grow into surrounding tissue to destroy it. Through the blood and lymphatic pathways, they seed metastases after a certain point. Despite medical advances, malignant cancer remains one of the most threatening diseases of all in the 21st century. Anthacyclins are used as cytostatic agents in malignant cancer due to their anti-proliferative mechanisms of action. As a mechanism of action, they primarily use the intercalation of tumor DNA, which blocks the protein biosynthesis of the cells, condemning them to death. Indications for the administration of daunorubicin include lymphocytic or myeloid leukemia in children, adolescents and adults. In most cases, daunorubicin is given together with other cytostatic drugs and represents an initiating agent within the chemotherapeutic induction phase, especially in acute lymphoblastic leukemia. Idarubicin, in turn, is used in the combination therapy of leukemias. Older patients with acute myeloid leukemia in particular receive this agent. As a rule, no pretreatment takes place prior to administration. However, the cytostatic drug is not suitable as a palliative therapy.Mitoxantrome is used not only for leukemia, but also for breast carcinoma, non-Hodgkin’s lymphoma and prostate carcinoma. It is also used for escalation therapy of patients with multiple sclerosis. Epirubicin is also used for breast carcinomas and non-Hodgkin’s lymphomas. Other indications include sarcomas and gastric carcinomas.
Risks and side effects
The side effects of anthracyclines depend on the specific agent. Daunorubicin may promote leukopenia, thrombocytopenia, and anemia. In addition, bleeding, infections due to immunological weakening, hair loss, or angina pectoris sometimes occur. The cardiovascular system may develop hypertension, arrhythmia, myocarditis, endocarditis, heart failure, and myocardial damage. In addition, pericardial effusions, pulmonary edema, and gastrointestinal tract discomfort are common side effects. In addition to nausea, vomiting, diarrhea, or abdominal pain may occur as the mucosa is attacked. Doxorubicin exhibits similar side effects and thus, like daunorubicin, is associated primarily with bone marrow depression and cardiotoxicity. With mitoxantrone, in addition to the aforementioned side effects, dizziness, discoloration of the urine and sclera, and skin necrosis frequently occur. In isolated cases, the drug also induces leukemia. Due to the manifold side effects and the threat of organ damage, there are countless contraindications to the administration of anthracyclines. Especially in cases of existing cardiac insufficiencies or cardiomyopathy, the administration of the active substances is hardly justifiable due to the cardiotoxicity to be expected. In addition, severe infections are usually a contraindication. This is because anthracyclines dampen the body’s immune system, so that existing infections can cause life-threatening sepsis (blood poisoning). Idarubicin is also not suitable for patients with bleeding tendencies, renal insufficiency or hepatic insufficiencies. In general, risks and benefits must be carefully weighed.
