Anthracyclines (or anthracycline antibiotics) are a class of drugs (CCNS or cell-cycle non-specific) used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var. caesius.
The anthracyclines are among the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapeutic agents. 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 first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Doxorubicin (trade name Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use.
Available agents include:
- Daunorubicin (Daunomycin)
- Daunorubicin (liposomal)
- Doxorubicin (Adriamycin)
- Doxorubicin (liposomal)
- Valrubicin, used only to treat bladder cancer
- Mitoxantrone, anthracycline analog
Mechanism of action
Anthracycline has four mechanisms of action:
- Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.
- Inhibits topoisomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication. Some sources say that topoisomerase II inhibitors prevent topoisomerase II from turning over which is needed for dissociation of topoisomerase II from its nucleic acid substrate. In other words, topoisomerase II stabilises the topoisomerase II complex after it has broken the DNA chain. This leads to topoisomerase II mediated DNA-cleavage, producing DNA breaks. The binding of topoisomerase II inhibitor prevents DNA repair by ligase.
- Creates iron-mediated free oxygen radicals that damage the DNA, proteins and cell membranes.
- Induces histone eviction from chromatin that deregulates DNA damage response, epigenome and transcriptome.
Anthracyclines are notorious for causing cardiotoxicity. This cardiotoxicity may be caused by many factors, which may include inhibition and/or poisoning of topoisomerase-IIB in cardiomyocytes, interference with the ryanodine receptors of the sarcoplasmic reticulum, free radical formation in the heart, or from buildup of metabolic products of the anthracycline in the heart. The cardiotoxicity often presents as ECG changes (especially change in the frequency of QRS complex) and arrhythmias, or as a cardiomyopathy leading to heart failure (sometimes presenting many years after treatment). This cardiotoxicity is related to a patient's cumulative lifetime dose. A patient's lifetime dose is calculated during treatment, and anthracycline treatment is usually stopped (or at least re-evaluated by the oncologist) upon reaching the maximum cumulative dose of the particular anthracycline.
There exists evidence that the effect of cardiotoxicity increases in long-term survivors, from 2% after 2 years to 5% after 15 years.
In addition to staying below the cumulative doses, various prevention measures may be employed by the oncologist in order to reduce the risk of cardiotoxicity. Cardiac monitoring are recommended at 3, 6, and 9 months. Other measures include the use of Dexrazoxane, the use of liposomal preparations of doxorubicin when appropriate, as well as the administration of doxorubicin over longer infusion rates:
- Dexrazoxane is a cardioprotectant that is sometimes used to reduce the risk of cardiotoxicity; it has been found to reduce the risk of anthracycline cardiotoxicity by about two-thirds, without affecting response to chemotherapy or overall survival.
- The liposomal formulations of daunorubicin and doxorubicin are less toxic to cardiac tissue than the non-liposomal form because a lower proportion of drug administered in the liposome form is delivered to the heart.
- Longer infusion rates will result in a reduced plasma level and a much lower left ventricular peak concentration.
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