Anthracycline Chemotherapy is used to treat a variety of cancers especially in combination with other drugs. These are anticancer compounds derived from the bacteria Streptomyces. They are red aromatic polyketides with different chemical structures due to aglycone and sugar residues.

Some Important Drugs in the Anthracycline Class

Daunomycin was the first anthracycline compound used to treat acute lymphoblastic and myeloblastic leukemia.

Doxorubicin or Adriamycin is a hydroxyl derivative of daunorubicin. This is used in combination with other drugs to treat solid tumors, breast cancer, small cell lung cancer ovarian cancer, bladder cancer, stomach cancer, liver cancer, thyroid cancer, Ewing’s cancer, osteogenic bone tumors, soft tissue sarcoma, neuroblastoma, Wilms tumor, multiple myeloma, leukemia, T-cell lymphoma, Hodgkin’s disease and non-Hodgkin’s lymphomas. Doxorubicin has great importance in the breast cancer chemotherapy treatment.

However, many tumors are resistant for these two drugs. These drugs cause damage to the heart as well as some other side effects. Hence, new drugs have been developed to reduce the cardiotoxic effect. Some of these drugs are epirubicin and idarubicin.

Epirubicin is similar to doxorubicin except for the orientation of the C-4 hydroxyl group on the sugar. Hence, this has lower cardiotoxicity. It is used to treat gastric cancer, breast cancer, carcinoid, endometrial cancer, lung cancer, ovarian cancer, esophageal cancer, prostate cancer and soft tissue sarcomas.

Idarubicin is an analog of daunorubicin. It does not have the C-4 methoxy group and hence has an affinity for lipids. It is used to treat as a part of induction therapy for acute myelogenous leukemia.

Valrubicin is N-trifluoroacetyl, 1-4-valerate derivative of doxorubicin. This penetrates the cells rapidly. It is used to treat bladder cancer.

Mechanism of Anthracyclines

Mechanism or the action of anthracyclines on the cancer cells is still under research although a lot of evidence is found.

Doxorubicin binds with the proteasome in the cytoplasm and this complex enters the nucleus. Proteasomes are mainly in the cytoplasm. Once the anthracyclines reach the nucleus they dissociate from the proteasome and bind with the DNA. This interrupts DNA synthesis. Binding to the proteasomes inhibits the protease activity that destroys the proteins involved in cell growth leading to apoptosis.

Intercalation into DNA

Anthracyclines like doxorubicin at low concentrations tend to dislocate the nuclear proteins. Daunorubicin is involved in aggregation of chromatin. This involves initial intercalation of the drug into the linker regions. This leads to changes in the DNA structure.

Interaction with DNA binding proteins

Anthracyclines inhibit DNA synthesis and RNA synthesis by affecting particular stages of the DNA replication process and RNA polymerase activity. Anthracycline rings that do not intercalate into the DNA stabilize the complex between Topoisomerase II and the DNA. This leads to DNA accumulation that is cytotoxic.

Side Effects of Anthracyclines

The side effects of anthracyclines, like any other chemotherapy drug are related to their cytotoxic effects i.e. damage to healthy cells and cancer cells both.

Some common side effects are nausea, vomiting and hair loss. Some of the major side effects include cardiotoxicity and myelosuppression.

Doxorubicin causes local tissue necrosis.

Cardiomyopathy and congestive heart failure are also two severe side effects of anthracyclines. Epirubicin is relatively less cardiotoxic. Anthracycline induced cardiotoxicity cannot be cured. The interaction between anthracyclines and iron causes cardiomyopathy by producing strong reactive oxygen species.

There is a drug to reduce this cardiomyopathy and there are various other factors considered to reduce this cardiotoxicity. Some of these are administering the right dosage, encapsulation into liposomes, combination with other drugs, use of cardio protectors and synthesis of modified anthracyclines.

Allergic Reactions are also one of the rare side effects for anthracyclines generally due to epirubicin and doxorubicin. High doses of epirubicin causes fever, hypertension and hypersensitivity.

Anthracycline chemotherapy is used in a number of cancers in various combinations. There are many new drugs of anthracycline class still under clinical research in an attempt to increase activity and reduce cardiotoxicity.