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Doxorubicin

Structure of Doxorubicin
Figure 1. Structure of Doxorubicin

Doxorubicin (trade name Adriamycin) or hydroxyldaunorubicin is a drug widely used in cancer chemotherapy. It is an anthracycline antibiotic that is structurally closely related to daunomycin; both compounds have been shown to intercalate into the DNA double helical structure. It is commonly used in the treatment of a wide range of cancers.

The drug is administered by injection. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex. Doxil is a liposome-encapsulated dosage form of doxorubicin, which displays a reduction in cardiotoxicity relative to Adriamycin alone.

 

History

The history of doxorubicin can be traced back to the 1950s, when an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th century castle. A new strain of Streptomyces peucetius, which produced a bright red pigment, was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against mouse tumors. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color. Clinical trials began in the 1960s, and the drug saw success in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity.

Modifications were made to the Streptomyces genetic machinery to produce a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a relatively higher therapeutic index, yet the cardiotoxicity remained. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research by many investigators throughout the world has led to many other anthracycline antibiotics, or analogs, and today, it is estimated that there are over 2,000 known analogs of doxorubicin.

 

Mechanism of action

Schematic diagram of Doxorubicin-DNA intercalation
Figure 2. Schematic diagram of Doxorubicin-DNA intercalation.

The exact mechanism of action of doxorubicin is complex and still somewhat unclear. One proposal is that it is thought to interact with DNA by intercalation. Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits 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.

The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.

 

Clinical use

Doxorubicin is commonly used to treat some leukemias, Hodgkin’s lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others. Commonly used doxorubicin-containing regimens are CA (cyclophosphamide, Adriamycin), TAC (Taxotere, CA), ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), BEACOPP, CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Doxil is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi’s sarcoma.

 

Experimental therapy

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice. 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 HIV within the host. The immunoconjugate could potentially provide a complimentary treatment to ART to eradicate antigen-expressing T cells.

 

Side effects

Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause neutropenia (a decrease in white blood cells), as well as complete alopecia (hair loss). When the cumulative dose of doxorubicin reaches 550 mg/m², the risks of developing cardiac side effects, including congestive heart failure, dilated cardiomyopathy, and death, dramatically increase. Doxorubicin cardiotoxicity is characterized 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.

Source: Wikipedia, Doxorubicin, http://en.wikipedia.org/wiki/Doxorubicin

 

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