Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer: breast cancer, bladder cancer, Kaposi’s sarcoma, lymphoma, and acute lymphocytic leukemia.
Pregnancy category AU: D
Routes of administration intravenous, intravesical
Bioavailability 5% (by mouth)
Protein binding 75%
Metabolism Liver
Elimination half-life
Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1–3 hours
Excretion
Urine (5–12%), faeces (40–50%)
Common side effects include hair loss, bone marrow suppression, vomiting, rash, and mucositis.
Other side effects may include allergic reactions such as anaphylaxis, heart damage, tissue damage at the site of injection, radiation recall, and treatment-related leukemia.
Red discoloration of the urine may occur for a few days.
Doxorubicin is in the anthracycline and antitumor antibiotic family of medications, that works in part by interfering with the function of DNA.
Doxorubicin is a cytotoxic anthracycline that inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA.
It blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition.
It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix.
It is also a powerful iron chelator.
The iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells.
Maximum toxicity occurs during the S phase of the cell cycle.
Versions that are pegylated and in liposomes are also available; however, they are more expensive.
Doxorubicin pegylated liposomal (as Caelyx) is indicated to treat breast cancer, ovarian cancer, and AIDS-related Kaposi’s sarcoma.
It is indicated to treat multiple myeloma in combination with bortezomib.
Doxorubicin hydrochloride is indicated to treat breast cancer in combination with cyclophosphamide.
Doxorubicin is commonly used to treat some leukemias and lymphomas, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma as well as desmoid tumor, multiple myeloma, and others.
Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP, CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) and FAC (5-fluorouracil, adriamycin, cyclophosphamide).
Doxorubicin 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.
Side effects
The most dangerous side effect of doxorubicin is dilated cardiomyopathy, leading to congestive heart failure.
The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m2, 18% when the dose is 551–600 mg/m2 and 36% when the dose exceeds 600 mg/m2.
Doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53-mediated apoptosis.
Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged,
This results in both systolic and diastolic dysfunction, with heart failure can result, which carries a 50% mortality rate.
There is no effective treatment against established cardiomyopathy caused by doxorubicin.
The drug dexrazoxane may be used to decrease the risk of doxorubicin’s cardiotoxicity in certain cases.
Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening inflammation of the bowel.
Palmar plantar erythrodysesthesia (PPE), characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and erythema may occur.
Chemotherapy can cause reactivation of hepatitis B.
Doxorubicin and several chemotherapeutic drugs can cause a loss of skin pigmentation.
There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, developed to treat Kaposi’s sarcoma.
The polyethylene glycol coating results in preferential concentration of doxorubicin in the skin, but also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome.
Following administration of this form of doxorubicin, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet, resulting in redness, tenderness, and peeling of the skin that can be painful.
At 50 mg/m2 dosing every four weeks, half of people developed hand-foot syndrome: The side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in the same treatment regimen, thereby limiting potential substitution.
Liposome-encapsulated doxorubicin, however, is less cardiotoxic than unencapsulated doxorubicin.
This liposome-encapsulated form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.
Trastuzumab cannot be used in concurrent combination with doxorubicin, only in sequential combination.
Though concurrent combination of trastuzumab and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as congestive heart failure (CHF).
Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.
It inhibits the progression of topoisomerase II, an enzyme 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 released and thereby stopping the process of replication.
By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin, damaging DNA response.
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