Антрациклины: класс противоопухолевых антибиотиков

Class of antibiotics

Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin. Their main adverse effect is cardiotoxicity, which considerably limits their usefulness. Use of anthracyclines has also been shown to be significantly associated with cycle 1 severe or febrile neutropenia. Other adverse effects include vomiting. The drugs act mainly by intercalating with DNA and interfering with DNA metabolism and RNA production. Cytotoxicity is primarily due to inhibition of topoisomerase II after the enzyme induces a break in DNA, preventing religation of the break and leading to cell death. The basic structure of anthracyclines is that of a tetracyclic molecule with an anthraquinone backbone connected to a sugar moiety by a glycosidic linkage. When taken up by a cell the four ring structure intercalates between DNA bases pairs while the sugar sits within the minor groove and interacts with adjacent base pairs.

Daunorubicin is a red pigmented drug which was discovered in the early 1960s. It was isolated from a strain of Streptomyces peucetius by Di Marco and coworkers, working for Farmitalia Research Laboratories in Italy who called it daunomycin. About the same time Dubost and coworkers in France also discovered the compound and named it rubidomycin. Daunorubicin was adopted as the international name. The first anthracyclines were so successful that thousands of analogues have been produced in attempts to find compounds with improved therapeutic applications. Only epirubicin and idarubicin have been adopted for worldwide use. Epirubicin has similar activity to doxorubicin, however has reduced cardiotoxic side effects. Idarubicin is a fat soluble variant of daunorubicin and is orally bioavailable. Several groups of researchers focused on designing compounds that retained the polycyclic aromatic chromophore of the anthracyclines (favouring intercalation into DNA) and substituting the sugar residue with simple side chains. This led to the identification of the mitoxantrone which is classed as an anthracenedione compound and is used in the clinic for the management of various cancers. Disaccharide analogues have been shown to retain anticancer activity, and are being further investigated with respect to their mechanism of action. Although it has been 50 years from the discovery of anthracyclines, and despite recent advances in the development of targeted therapies for cancers, around 32% of breast cancer patients, 57% 70% of elderly lymphoma patients and 50–60% of childhood cancer patients are treated with anthracyclines. Some cancers benefit from neoadjuvant anthracycline based regimes, and these include triple negative breast cancers that do not respond well to targeted therapies due to the lack of available receptors that can be targeted. Compared to non triple negative breast cancer patients, triple negative breast cancer patients have shown better response rate and higher pathological response rate with anthracycline use, an indicator used for predicting improved long term outcomes.

The anthracyclines have been widely studied for their interactions with cellular components and impact on cellular processes. This includes studies in cultured cells and in whole animal systems. A myriad of drug cellular interactions have been documented in the scientific literature and these vary with respect to the properties of target cells, drug dose and drug intermediates produced. Since artefactual mechanisms of action can be observed, the following mechanisms which occur at clinically relevant drug concentrations are the most important.

Anthracyclines are readily taken up by cells and localised to the nucleus. The chromophore moiety of anthracyclines has intercalating function and inserts in between the adjacent base pair of DNA. This topoisomerase II mediated DNA damage subsequently promotes growth arrest and recruits DNA repair machinery. When the repair process fails, the lesions initiate programmed cell death. In addition, the availability of cellular iron catalyses redox reactions and further generates ROS. The supply of extracellular formaldehyde using formaldehyde releasing prodrugs can promote covalent DNA adduct formation. Such adducts have been shown to block GpC specific transcription factors and induce apoptotic responses.