Doxorubicin

Doxorubicin or adriamycin or hydroxyldaunorubicin is a DNA-interacting drug widely used in chemotherapy. It is an anthracycline and structurely closely related to daunomycin, and also intercalates DNA. It is commonly used in the treatment of a wide range of cancers.

Doxil® is a liposome-encapsulated dosage form of doxorubicin made by Johnson & Johnson. Its main benefits are a reduction in cardiotoxicity. It follows the similar preparation of daunorubicin in a liposomal carrier.

Mechanism of Action

Doxorubicin acts by binding to DNA where it can inhibit the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.

Side effects

Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause a decrease in white blood cells and alopecia (hair loss). When the cumulative dose of doxorubicin reaches 450mg/m2, the risks of developing cardiac side effects, including congestive heart failure, dilated cardiomyopathy, and death, dramatically increase. Doxorubicin cardiotoxicity is characterised by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes (heart cells), causing myofibrillar loss and cytoplasmic vacuolization. Additionally, some adults who were treated with doxorubicin when they were children have developed dilated cardiomyopathy up to 15 years later.

Clinical Use

Doxorubicin is a commonly used to treat Hodgkin's disease, breast cancer, lung cancer, soft tissue sarcoma, Kahler's disease (multiple myeloma) and recurring instances of ovarian cancer. Commonly used doxorubicin-containing regimens are ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide).

Experimental

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas. See sirolimus.

Recent animal research coupling a murine monoclonal antibody with doxorubicin has created an immunoconjugate that was able to eliminate HIV-1 infection in mice. Current treatment with antiretroviral therapy (ART) still leaves pockets of the HIV virus within the host. The immunoconjugate could potentially provide a complimentary treatment to ART to eradicate antigen-expressing T cells.

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