Doxorrubicin

Doxorubicin (INN, pronounced /ˌdɒksəˈruːbəsɪn/; trade name Adriamycin; also known as hydroxydaunorubicin) is a drug used in cancer chemotherapy. It is ananthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA.

Doxorubicin is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas.

Doxorubicin's most serious adverse effect is life-threatening heart damage.

The drug is administered intravenously, in the form of hydrochloride salt. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex.^[2]Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.

The molecule was originally isolated in the 1950s from bacteria found in soil samples taken from Castel del Monte, an Italian castle

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 ofStreptomyces peucetius, which produced a red pigment, was isolated, and an antibiotic was produced from this bacterium that was found to have good activity againstmurine 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.^[3] 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.^[4]

Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain ofStreptomyces was mutated using N-nitroso-N-methyl urethane, and this new strain produced 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.^[5] Doxorubicin showed better activity than daunorubicin against murine tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.^[6]

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 it is now estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI).^[3]

Clinical use

Doxorubicin is commonly used to treat some leukemias and Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others.^[2] Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), 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.^[7]

Adverse effects

Acute adverse 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 CHF, 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. Additionally, some patients may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain and erythema.^[7]

Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"^[12] or "red death."^[13]

Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception

Mechanism of action

The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation.^[23] Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis.^[24] This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in 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