Anthracycline

Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium ''Streptomyces peucetius var. caesius''.

These compounds are used to treat many cancers, including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers.

The anthracyclines are some of 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. 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 (Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use.

Examples
Available agents include:


 * Daunorubicin (Daunomycin)
 * Daunorubicin (liposomal)
 * Doxorubicin (Adriamycin)
 * Doxorubicin (liposomal)
 * Epirubicin
 * Idarubicin
 * Valrubicin, used only to treat bladder cancer
 * Mitoxantrone, anthracycline analog

Since they are antibiotics, anthracyclines can kill or inhibit the growth of bacteria, but, because they are so toxic to humans, they are never used to treat infections.

Mechanism of action
Anthracycline has three mechanisms of action:


 * 1) Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.
 * 2) Inhibits topoisomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication. Some sources say that topo II inhibitors prevent topo II from turning over which is needed for dissociation of topo II from its nucleic acid substrate. In other words, topo II stabilises the topo II complex after it has broken the DNA chain. This leads to topo II mediated DNA-cleavage, producing DNA breaks. The binding of topo II inhibitor prevents DNA repair by ligase.
 * 3) Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes.

Cardiotoxicity
Anthracyclines are notorious for causing cardiotoxicity. This cardiotoxicity may be caused by many factors, which may include interference with the ryanodine receptors of the sarcoplasmic reticulum in the heart muscle cells, from 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.