 | |
 | |
| Clinical data | |
|---|---|
| Pronunciation | /ˌdɒksəˈruːbəsɪn/ |
| Trade names | Adriamycin, Caelyx,[1] Myocet,[2] others |
| Biosimilars | Zolsketil pegylated liposomal,[3] Celdoxome pegylated liposomal[4] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682221 |
| License data | |
| Pregnancy category |
|
| Routes of administration | intravenous,intravesical |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 5% (by mouth) |
| Protein binding | 75%[8] |
| Metabolism | Liver |
| Eliminationhalf-life | Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1–3 hours[8][9] |
| Excretion | Urine (5–12%), faeces (40–50%)[8] |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider | |
| UNII |
|
| KEGG | |
| ChEBI |
|
| ChEMBL |
|
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.041.344 |
| Chemical and physical data | |
| Formula | C27H29NO11 |
| Molar mass | 543.525 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
 N Y (what is this?) (verify) | |
Doxorubicin, sold under the brand nameAdriamycin among others, is achemotherapy medication used to treatcancer.[10] This includesbreast cancer,bladder cancer,Kaposi's sarcoma,lymphoma, andacute lymphocytic leukemia.[10] It is often usedtogether with other chemotherapy agents.[10] Doxorubicin is given byinjection into a vein.[10]
Common side effects includehair loss,bone marrow suppression,vomiting, rash, andinflammation of the mouth.[10] Other serious side effects may includeallergic reactions such asanaphylaxis,heart damage, tissue damage at the site of injection,radiation recall, and treatment-relatedleukemia.[10] People often experience red discoloration of the urine for a few days.[10] Doxorubicin is in theanthracycline andantitumor antibiotic family of medications.[10] It works in part by interfering with the function ofDNA.[11]
Doxorubicin was approved for medical use in the United States in 1974.[10] It is on theWorld Health Organization's List of Essential Medicines.[12][13] Versions that arepegylated and inliposomes are also available; however, they are more expensive.[13] Doxorubicin was originally made from the bacteriumStreptomyces peucetius.[14]
In the EU doxorubicin pegylated liposomal (as Caelyx) isindicated to treat breast cancer, ovarian cancer, and AIDS-related Kaposi's sarcoma. It is indicated to treatmultiple myeloma in combination withbortezomib.[1] Doxorubicin hydrochloride (as Myocet liposomal) is indicated to treat breast cancer in combination withcyclophosphamide.[2]
Doxorubicin is commonly used to treat someleukemias andlymphomas, as well as cancers of thebladder,breast,stomach,lung,ovaries,thyroid,soft tissue sarcoma as well asaggressive fibromatosis (desmoid tumor),multiple myeloma, and others.[9][15][16] 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).[9] Its activity is inhibited by certain antioxidant plant extracts, for exampleTragia volubilis aqueous extract.[17]
Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred afterplatinum-based chemotherapy, or for the treatment ofAIDS-relatedKaposi's sarcoma.[18]
The most dangerous side effect of doxorubicin isdilated cardiomyopathy, leading tocongestive 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.[19] There are several ways in which doxorubicin is believed to cause cardiomyopathy, includingoxidative stress due to iron accumulation, downregulation of genes for contractile proteins, andp53-mediatedapoptosis.[19][20]
Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged.[21] This results in both systolic and diastolic dysfunction.[21] Eventually, heart failure can result, which carries a 50% mortality rate.[21] There is no effective treatment against established cardiomyopathy caused by the drug as of 2010.[21] The drugdexrazoxane, which is an ironchelator, may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases.[22]
Another common and potentially fatal complication of doxorubicin istyphlitis, an acute life-threatening inflammation of the bowel.[23] Additionally, some people may developpalmar plantar erythrodysesthesia (PPE), characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, anderythema.[18] Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"[24] or "red death."[25]
Chemotherapy can cause reactivation ofhepatitis B, and doxorubicin-containing regimens are no exception.[26][27]
Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss ofskin pigmentation.[28]
Doxorubicin has been linked to myopathy of the bladder's detrusor muscle, causing dysfunction of its contractile-relaxation mechanism and higher risk oflower urinary tract dysfunction (LUTD) than peers. It is recommended that childhood cancer survivors treated with doxorubicin be monitored for subsequent LUTD.[29]
There is apegylated (polyethylene glycol coated)liposome-encapsulated form of doxorubicin, developed to treatKaposi's sarcoma. Thepolyethylene glycol coating results in preferential concentration of doxorubicin in the skin. However, this also results in a side effect calledpalmar 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. 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 four weeks, half of people developed hand-foot syndrome. The rate of this 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. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. This liposome-encapsulated form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.[30][31]
A non-pegylated liposomal doxorubicin, called Myocet, is approved in the European Union and in Canada for the treatment of metastatic breast cancer in combination withcyclophosphamide,[2] but it has not been approved by the FDA for use in the United States. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same rate of PPE. The minimization of this side effect may allow for one-for-one (1:1) 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 astrastuzumab. There is an FDAboxed warning that 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 ascongestive heart failure (CHF). Published phase II study results have shown that Myocet, trastuzumab, andpaclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction inLVEF function, while still achieving superior tumor response. This finding is the basis for the ongoing phase III trial for FDA approval.[30]
Doxorubicin (DXR) is a 14-hydroxylated version ofdaunorubicin, the immediate precursor of DXR in itsbiosynthetic pathway.
Daunorubicin is more abundantly found as anatural product because it is produced by a number of differentwild typestrains ofStreptomyces. In contrast, only one known non-wild typespecies,Streptomyces peucetiussubspeciescesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin.[32] This strain was created by Arcamone et al. in 1969 bymutating a strain producing daunorubicin, but not DXR, at least in detectable quantities.[33] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction ofgenetic modifications, other strains ofStreptomyces can produce doxorubicin.[34] His group alsocloned many of thegenes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, thegene encoding theenzyme that converts daunorubicin into DXR.[35]
By 1999, they produced recombinant dox A, acytochrome P450 oxidase, and found that itcatalyzes multiple steps in DXRbiosynthesis, including steps leading to daunorubicin.[36] This was significant because it became clear that all daunorubicin-producing strains have the necessarygenes 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 thefermentation process used in its commercial production, not only by introducing dox A encodingplasmids, but also by introducing mutations to deactivateenzymes that shunt DXR precursors to less useful products, for example baumycin-likeglycosides.[32] Some triple mutants, that alsoover-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.[37]
More efficient production techniques have brought the price down to $1.1 million per kg for the nonliposomal formulation. Although DXR can be producedsemi-synthetically from daunorubicin, the process involveselectrophilicbromination and multiple steps, and the yield is poor.[38] Since daunorubicin is produced byfermentation, it would be ideal if thebacteria could complete DXR synthesis more effectively.
Doxorubicin interacts with DNA byintercalation and inhibition of macromolecularbiosynthesis.[11][40][41] This inhibits the progression oftopoisomerase II, an enzyme which relaxes supercoils in DNA fortranscription.[42] 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 ofreplication.[11] It may also increase quinone type free radical production, hence contributing to its cytotoxicity.[15]
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.[39][43]
Byintercalation, doxorubicin can also inducehistone eviction from transcriptionally activechromatin.[44][45] As a result, theDNA damage response,epigenome andtranscriptome are deregulated in doxorubicin-exposed cells.[44]
In the 1950s, 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 theCastel del Monte, a 13th-century castle. A new strain ofStreptomyces peucetius, which produced a red pigment, was isolated, and an antibiotic from this bacterium was effective against tumors in mice. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compounddaunorubicin, combining the nameDauni, 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.[46][47][48] Clinical trials began in the 1960s, and the drug was successful in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could lead to fatal cardiac toxicity.[49]
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 usingN-nitroso-N-methyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after theAdriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention.[33] Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a highertherapeutic index, yet thecardiotoxicity remained.[50]
Doxorubicin and daunorubicin together can be thought of as prototype compounds for theanthracyclines. Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at theNational Cancer Institute (NCI).[46] In 2016 GPX-150 was grantedorphan drug designation by US FDA.[51]
On 24 March 2022, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zolsketil pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma.[52] The applicant for this medicinal product is Accord Healthcare S.L.U.[52] Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin.[52] It contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.[52] Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022.[3][53]
On 21 July 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Celdoxome pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma.[54] The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH.[54] Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979.[54] Celdoxome pegylated liposomal contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.[54] Celdoxome pegylated liposomal was approved for medical use in the European Union in September 2022.[4]
It is also known as hydroxydaunorubicin and hydroxydaunomycin.[55]
It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.[9]
Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.[9] Doxorubicin is also available inliposome-encapsulated forms as Doxil (pegylated form), Myocet (nonpegylated form), and Caelyx,[1] which are also given by intravenous injection.[9]
The FDA approved the first generic version of Doxil, made by Sun, in February 2013.[56]
Combination therapy experiments withsirolimus (rapamycin) and doxorubicin have shown promise in treatingAkt-positivelymphomas in mice.[57]
Further, the release of photo-activated adriamycin with the aid of nanoporous optical antenna resulted in significant anti-cancer effect in MCF-7 breast cancer cells.[58] In 2006, animal research coupling amurinemonoclonal antibody with doxorubicin created animmunoconjugate that was able to eliminateHIV-1 infection in mice.[59][60]
There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibitplasmepsin II, an enzyme unique to the malarial parasitePlasmodium falciparum.[61] The pharmaceutical companyGlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth.[62]
Doxorubicin is also known to be fluorescent. This has often been used to characterize doxorubicin concentrations, and has opened the possibility of using the molecule as atheranostic agent. However, there are significant limitations, as doxorubicin's fluorescence spectrum is known to depend on a variety of factors, including the pH of the environment, solventdielectric constant and others. Doxorubicin fluorescence is quenched by binding to DNA, and shielded by micelle encapsulation. It is also known to self-quench at high concentrations. In contrast, histone binding amplifies fluorescence.[63][64]
Media related toDoxorubicin at Wikimedia Commons| International | |
|---|---|
| National | |
| Other | |
