Doxorubicin /ˌdɒksəˈruːbɨsɪn/ (INN, AAN, BAN, USAN; trade name Adriamycin; pegylated liposomal form trade name Doxil; nonpegylated liposomal form trade name Myocet), also known as hydroxydaunorubicin and hydroxydaunomycin, is a drug used in cancer chemotherapy and derived by chemical semisynthesis from a bacterial species.[2] It is an anthracycline antitumor antibiotic(note: in this context, this does not mean it is used to treat bacterial infections) closely related to the natural product daunomycin and like all anthracyclines, it works by intercalating DNA, with the most serious adverse effect being life-threatening heart damage. It is commonly used in the treatment of a wide range of cancers, including hematological malignancies (blood cancers, like leukaemiaand lymphoma), many types of carcinoma (solid tumours) and soft tissue sarcomas.[3] It is often used in combination chemotherapyas a component of various chemotherapy regimens.
Common adverse effects of doxorubicin include hair loss (seen in most of those treated with the drug), myelosuppression (a compromised ability of the body's bone marrow to produce new blood cells), nausea and vomiting (which are seen in roughly 30-90% of people treated with the drug), oral mucositis, oesophagitis, diarrhoea, skin reactions (including hand-foot syndrome) and localised swelling and redness along the vein in which the drug is delivered.[2][4] Less common, yet serious reactions include hypersensitivity reactions (including anaphylaxis), radiation recall, heart damage and liver dysfunction.[4]
The drug is administered intravenously, as the hydrochloride salt.[2] It is sold under a number of different brand names, includingAdriamycin 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.[2] Doxorubicin is also available in liposome-encapsulated forms as Doxil (pegylated form), Myocet (nonpegylated form), and Caelyx, although these forms must also be given by intravenous injection.
Medical use[edit]
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][4] Commonly used doxorubicin-containingregimens are AC (Adriamycin, cyclophosphamide), TAC (Taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine),BEACOPP, CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) and FAC (5-fluorouracil, Adriamycin,cyclophosphamide).[2]
Doxil (see below) 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.[5]
Doxil shortage in the US[edit]
As of February 2014, Doxil was available for clinical use in limited supply.[6] In 2011, Doxil became available only in very limited supply due to production problems with the third-party manufacturer. Johnson & Johnson (JNJ), through its subsidiary Janssen Products, LP, had been receiving its Doxil supply from contract manufacturer Ben Venue Laboratories (located in Bedford, Ohio), a unit of Boehringer Ingelheim GmbH of Germany.[7] The problems began when Ben Venue temporarily shut down their manufacturing facility due to quality control issues.[8]
In February 2012, to address the Doxil shortage, the US Food and Drug Administration (FDA) allowed for the temporary importation of Lipodox, which contains the same active ingredient as Doxil and is made by Sun Pharma Global FZE (Sun), a subsidiary of India's Sun Pharmaceutical Industries Ltd.[9] The agency said it intends to continue allowing the importation of Lipodox until Sun has made enough generic Doxil to meet demand.[10]
The FDA approved the first generic version of Doxil, made by Sun, in February 2013. It will be available in 20 milligram and 50 milligram vials.[11]
Experimental therapy[edit]
Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.[12]
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 complementary treatment to ART to eradicate antigen-expressing T cells.[13]
Liposomal formulations[edit]
Doxil is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin formerly made by Ben Venue Laboratories in the United States for Janssen Products, LP, a subsidiary of Johnson & Johnson. It was developed to treat Kaposi's sarcoma, an AIDS-related cancer that causes lesions to grow under the skin, in the lining of the mouth, nose and throat, or in other organs. The polyethylene glycol coating results in preferential concentration of Doxil in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome. Following administration of Doxil, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m2 dosing every 4 weeks, 50.6% of patients treated with Doxil developed hand-foot syndrome. The prevalence of this side effect limits the Doxil dose that can be given as compared with doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. Doxil is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.[14][15]
Myocet is a non-pegylated liposomal doxorubicin made by Enzon Pharmaceuticals for Cephalon in Europe and for Sopherion Therapeutics in the United States and Canada. Myocet is approved in Europe and Canada for treatment of metastatic breast cancer in combination with cyclophosphamide, but is not yet approved by the FDA for use in the United States. It is currently being studied by Sopherion Therapeutics in a pivotal phase III global registrational trial in concurrent combination with trastuzumab (Herceptin) andpaclitaxel (Taxol) for treatment of HER2-positive metastatic breast cancer. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same prevalence of hand-foot syndrome. The minimization of this side effect may allow for one for one substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as trastuzumab. There is an FDA black box warning that Herceptin 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). Published phase II study results have shown that Myocet, trastuzumab, and paclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for the on-going phase III trial for FDA approval.[14]
Experimental models of cell death in situ[edit]
Intraperitoneal injection of doxorubicin in mice induces cell death of monocytes and macrophages. The acute sterile inflammation in this model is characterized by rapid influx of neutrophils and increased levels of IL-6 and monocyte chemotactic protein-1. It was demonstrated that acute inflammation induced by doxorubicin is associated with apoptosis of monocytes/macrophages and that it is specific for doxorubicin, an immunogenic chemotherapeutic. Further, the inflammatory response is significantly reduced in mice deficient in myeloid differentiation primary response gene 88 (MyD88), TLR-2 or TLR-9. Importantly, a TLR-9 antagonist reduces the recruitment of neutrophils induced by doxorubicin. By contrast, the acute inflammatory response is not affected in TRIF(Lps2) mutant mice and in TLR-3, TLR-4 and caspase-1 knockout mice, which shows that the inflammasome does not have a major role in doxorubicin-induced acute inflammation.[16]
Antimalarial activity[edit]
There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibit plasmepsin II, an enzyme unique to the malarial parasite Plasmodium falciparum.[17] The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth [18]
Adverse effects[edit]
The most dangerous side effect of doxorubicin is cardiomyopathy, leading to congestive heart failure. The incidence of this 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.[19] There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53 mediatedapoptosis.[19] The drug dexrazoxane is used to mitigate doxorubicin's cardiotoxicity.
Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening infection of the bowel.[20]
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.[5]
Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"[21] or "red death."[22]
Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.[23][24]
Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) cause dyspigmentation. Other groups of drugs that cause this problem include antimalarials, amiodarone, heavy metals (but not iron), tetracyclines, and antipsychotics.[25]
Biosynthesis[edit]
Main article: Biosynthesis of doxorubicin
Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of Streptomyces. In contrast, only one known non-wild type species, Streptomyces peucetius subspeciescesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin.[26] This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities.[27] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of Streptomyces can produce doxorubicin.[28] His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR.[29] By 1999, they produced recombinant dox A, a cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin.[30] This was significant because it became clear that all daunorubicin-producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides.[26] Some triple mutants, that also over-expressed dox A, were able to double the yield of DXR. This is of more than academic interest, because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum.[31] More efficient production techniques have brought the price down to $1.1 million per kg for the nonliposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps, and the yield is poor.[32] Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.
Mechanism of action[edit]
Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.[3][34][35] This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription.[36] 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 ofreplication.[3] It may also increase free radical production, hence contributing to its cytotoxicity.[4]
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.[33][37]
By intercalation, doxorubicin can also induce histone eviction from chromatin. As a result, DNA damage response, epigenome andtranscriptome are deregulated in doxorubicin-exposed cells.
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