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Doxorubicin

February 15, 2024

Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer.[10] This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia.[10] It is often used together with other chemotherapy agents.[10] Doxorubicin is given by injection into a vein.[10]

Doxorubicin
Clinical data
Pronunciation/ˌdɒksəˈruːbɪsɪn/
Trade namesAdriamycin, Caelyx,[1] Myocet,[2] others
BiosimilarsZolsketil pegylated liposomal,[3] Celdoxome pegylated liposomal[4]
AHFS/Drugs.comMonograph
MedlinePlusa682221
License data
Pregnancy
category
  • AU: D
Routes of
administration		intravenous, intravesical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5% (by mouth)
Protein binding75%[8]
MetabolismLiver
Elimination half-lifeTriphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1–3 hours[8][9]
ExcretionUrine (5–12%), faeces (40–50%)[8]
Identifiers
  • (7S,9S)-7-[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
CAS Number
  • 23214-92-8 Y
  • as HCl: 25316-40-9
PubChem CID
  • 31703
  • as HCl: 443939
IUPHAR/BPS
  • 7069
DrugBank
  • DB00997 Y
  • as HCl: DBSALT000060
ChemSpider
  • 29400 Y
  • as HCl: 391993
UNII
  • 80168379AG
  • as HCl: 82F2G7BL4E
KEGG
  • D03899 Y
  • as HCl: D01275
ChEBI
  • CHEBI:28748 Y
  • as HCl: CHEBI:31522
ChEMBL
  • ChEMBL53463 N
  • as HCl: ChEMBL359744
CompTox Dashboard (EPA)
  • DTXSID8021480
ECHA InfoCard100.041.344
Chemical and physical data
FormulaC27H29NO11
Molar mass543.525 g·mol−1
3D model (JSmol)
  • Interactive image
  • C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](Cc3c2c(c4c(c3O)C(=O)c5cccc(c5C4=O)OC)O)(C(=O)CO)O)N)O
  • InChI=1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27 (36,16(30)9–29)7-12-19(15)26(35)21–20(24(12)33)23 (32)11-4-3-5-14(37–2)18(11)25(21)34/h3-5,10,13,15, 17,22,29,31,33,35-36H,6–9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1 N
  • Key:AOJJSUZBOXZQNB-TZSSRYMLSA-N Y
 NY (what is this?)  (verify)

Common side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth.[10] Other serious side effects may include allergic reactions such as anaphylaxis, heart damage, tissue damage at the site of injection, radiation recall, and treatment-related leukemia.[10] People often experience red discoloration of the urine for a few days.[10] Doxorubicin is in the anthracycline and antitumor antibiotic family of medications.[10] It works in part by interfering with the function of DNA.[11]

Doxorubicin was approved for medical use in the United States in 1974.[10] It is on the World Health Organization's List of Essential Medicines.[12][13] Versions that are pegylated and in liposomes are also available; however, they are more expensive.[13] Doxorubicin was originally made from the bacterium Streptomyces peucetius.[14]

Medical uses edit

In the EU 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.[1] Doxorubicin hydrochloride (as Myocet liposomal) is indicated to treat breast cancer in combination with cyclophosphamide.[2]

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, multiple myeloma, and others.[9][15] 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).[9] Its activity is inhibited by certain antioxidant plant extracts, for example Tragia volubilis aqueous extract.[16]

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.[17]

Side effects edit

Cardiotoxicity edit

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.[18] There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53-mediated apoptosis.[18]

Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged.[19] This results in both systolic and diastolic dysfunction.[19] Eventually, heart failure can result, which carries a 50% mortality rate.[19] There is no effective treatment against established cardiomyopathy caused by the drug as of 2010.[19] The drug dexrazoxane may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases.[20]

Other edit

Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening inflammation of the bowel.[21] Additionally, some people may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and erythema.[17] Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"[22][23] or "red death."[24]

Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.[25][26]

Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of skin pigmentation.[27]

Liposomal formulations edit

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. However, this 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. 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, 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.[28][29]

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 with cyclophosphamide,[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 as trastuzumab. There is an FDA black box 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 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 ongoing phase III trial for FDA approval.[28]

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 subspecies cesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin.[30] This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities.[31] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of Streptomyces can produce doxorubicin.[32] His group 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.[33]

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.[34] 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.[30] 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.[35]

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.[36] Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.

Mechanism of action edit

 
Diagram of two doxorubicin molecules intercalating DNA, from PDB: 1D12​.[37]

Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.[11][38][39] This inhibits the progression of topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription.[40] 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.[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.[37][41]

By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin.[42][43] As a result, the DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.[42]

History edit

 
Bacteria producing doxorubicin were originally discovered in soil near Castel del Monte, Apulia.
See also: Anthracycline § History, Daunorubicin § History, and History of cancer chemotherapy

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 the Castel del Monte, a 13th-century castle. A new strain of Streptomyces 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 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.[44][45][46] 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.[47]

Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces 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.[31] Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.[48]

Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. 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 the National Cancer Institute (NCI).[44] In 2016 GPX-150 was granted orphan drug designation by US FDA.[49]

Society and culture edit

Legal status edit

On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European 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.[50] The applicant for this medicinal product is Accord Healthcare S.L.U.[50] Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin.[50] It contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.[50] Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022.[3][51]

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.[52] The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH.[52] Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979.[52] Celdoxome pegylated liposomal contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.[52] Celdoxome pegylated liposomal was approved for medical use in the European Union in September 2022.[4]

Names edit

It is also known as hydroxydaunorubicin and hydroxydaunomycin.[53]

It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.[9]

Formulations edit

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 in liposome-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.[54]

Research edit

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.[55]

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.[56] In 2006, animal research coupling a murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV-1 infection in mice.[57][58]

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.[59] The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth.[60]

Fluorescence edit

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 a theranostic 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, solvent dielectric 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.[61][62]

References edit

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  56. ^ Saha T, Mondal J, Khiste S, Lusic H, Hu ZW, Jayabalan R, et al. (September 2021). "Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer". Nanophotonics. 10 (12): 3063–3073. Bibcode:2021Nanop..10..142S. doi:10.1515/nanoph-2021-0142. PMC 8478290. PMID 34589378.
  57. ^ Johansson S, Goldenberg DM, Griffiths GL, Wahren B, Hinkula J (October 2006). "Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody". AIDS. 20 (15): 1911–1915. doi:10.1097/01.aids.0000247111.58961.60. PMID 16988511. S2CID 42286690.
  58. ^ Mitsuyasu R (May 2013). "Curing HIV: lessons from cancer therapy". Current Opinion in HIV and AIDS. 8 (3): 224–229. doi:10.1097/COH.0b013e32835ef0a1. PMC 3789644. PMID 23454863.
  59. ^ Friedman R, Caflisch A (August 2009). "Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring". ChemMedChem. 4 (8): 1317–1326. doi:10.1002/cmdc.200900078. PMID 19472268. S2CID 14642593. Archived from the original on 5 January 2013. Retrieved 28 May 2010.
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External links edit

  •   Media related to Doxorubicin at Wikimedia Commons
  • "Doxorubicin". Drug Information Portal. U.S. National Library of Medicine.
  • "Doxorubicin hydrochloride". Drug Information Portal. U.S. National Library of Medicine.

February 15, 2024
doxorubicin, sold, under, brand, name, adriamycin, among, others, chemotherapy, medication, used, treat, cancer, this, includes, breast, cancer, bladder, cancer, kaposi, sarcoma, lymphoma, acute, lymphocytic, leukemia, often, used, together, with, other, chemo. Doxorubicin sold under the brand name Adriamycin among others is a chemotherapy medication used to treat cancer 10 This includes breast cancer bladder cancer Kaposi s sarcoma lymphoma and acute lymphocytic leukemia 10 It is often used together with other chemotherapy agents 10 Doxorubicin is given by injection into a vein 10 DoxorubicinClinical dataPronunciation ˌ d ɒ k s e ˈ r uː b ɪ s ɪ n Trade namesAdriamycin Caelyx 1 Myocet 2 othersBiosimilarsZolsketil pegylated liposomal 3 Celdoxome pegylated liposomal 4 AHFS Drugs comMonographMedlinePlusa682221License dataEU EMA by INN US DailyMed DoxorubicinPregnancycategoryAU DRoutes ofadministrationintravenous intravesicalATC codeL01DB01 WHO Legal statusLegal statusAU S4 Prescription only CA only 5 6 7 UK POM Prescription only US only EU Rx only 1 2 3 4 In general Prescription only Pharmacokinetic dataBioavailability5 by mouth Protein binding75 8 MetabolismLiverElimination half lifeTriphasic 12 minutes 3 3 hours 30 hours Mean 1 3 hours 8 9 ExcretionUrine 5 12 faeces 40 50 8 IdentifiersIUPAC name 7S 9S 7 2R 4S 5S 6S 4 Amino 5 hydroxy 6 methyloxan 2 yl oxy 6 9 11 trihydroxy 9 2 hydroxyacetyl 4 methoxy 8 10 dihydro 7H tetracene 5 12 dioneCAS Number23214 92 8 Yas HCl 25316 40 9PubChem CID31703as HCl 443939IUPHAR BPS7069DrugBankDB00997 Yas HCl DBSALT000060ChemSpider29400 Yas HCl 391993UNII80168379AGas HCl 82F2G7BL4EKEGGD03899 Yas HCl D01275ChEBICHEBI 28748 Yas HCl CHEBI 31522ChEMBLChEMBL53463 Nas HCl ChEMBL359744CompTox Dashboard EPA DTXSID8021480ECHA InfoCard100 041 344Chemical and physical dataFormulaC 27H 29N O 11Molar mass543 525 g mol 13D model JSmol Interactive imageSMILES C C H 1 C H C H C C H O1 O C H 2C C Cc3c2c c4c c3O C O c5cccc c5C4 O OC O C O CO O N OInChI InChI 1S C27H29NO11 c1 10 22 31 13 28 6 17 38 10 39 15 8 27 36 16 30 9 29 7 12 19 15 26 35 21 20 24 12 33 23 32 11 4 3 5 14 37 2 18 11 25 21 34 h3 5 10 13 15 17 22 29 31 33 35 36H 6 9 28H2 1 2H3 t10 13 15 17 22 27 m0 s1 NKey AOJJSUZBOXZQNB TZSSRYMLSA N Y N Y what is this verify Common side effects include hair loss bone marrow suppression vomiting rash and inflammation of the mouth 10 Other serious side effects may include allergic reactions such as anaphylaxis heart damage tissue damage at the site of injection radiation recall and treatment related leukemia 10 People often experience red discoloration of the urine for a few days 10 Doxorubicin is in the anthracycline and antitumor antibiotic family of medications 10 It works in part by interfering with the function of DNA 11 Doxorubicin was approved for medical use in the United States in 1974 10 It is on the World Health Organization s List of Essential Medicines 12 13 Versions that are pegylated and in liposomes are also available however they are more expensive 13 Doxorubicin was originally made from the bacterium Streptomyces peucetius 14 Contents 1 Medical uses 2 Side effects 2 1 Cardiotoxicity 2 2 Other 2 3 Liposomal formulations 3 Biosynthesis 4 Mechanism of action 5 History 6 Society and culture 6 1 Legal status 6 2 Names 6 3 Formulations 7 Research 7 1 Antimalarial activity 7 2 Fluorescence 8 References 9 External linksMedical uses editIn the EU 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 1 Doxorubicin hydrochloride as Myocet liposomal is indicated to treat breast cancer in combination with cyclophosphamide 2 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 multiple myeloma and others 9 15 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 9 Its activity is inhibited by certain antioxidant plant extracts for example Tragia volubilis aqueous extract 16 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 17 Side effects editCardiotoxicity edit 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 18 There are several ways in which doxorubicin is believed to cause cardiomyopathy including oxidative stress downregulation of genes for contractile proteins and p53 mediated apoptosis 18 Doxorubicin induced cardiomyopathy typically results in dilated cardiomyopathy with all four cardiac chambers being enlarged 19 This results in both systolic and diastolic dysfunction 19 Eventually heart failure can result which carries a 50 mortality rate 19 There is no effective treatment against established cardiomyopathy caused by the drug as of 2010 19 The drug dexrazoxane may be used to decrease the risk of doxorubicin s cardiotoxicity in certain cases 20 Other edit Another common and potentially fatal complication of doxorubicin is typhlitis an acute life threatening inflammation of the bowel 21 Additionally some people may develop PPE characterized by skin eruptions on the palms of the hand or soles of the feet swelling pain and erythema 17 Due to these side effects and its red color doxorubicin has earned the nickname red devil 22 23 or red death 24 Chemotherapy can cause reactivation of hepatitis B and doxorubicin containing regimens are no exception 25 26 Doxorubicin and several chemotherapeutic drugs including cyclophosphamide can cause a loss of skin pigmentation 27 Liposomal formulations edit 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 However this 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 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 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 28 29 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 with cyclophosphamide 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 as trastuzumab There is an FDA black box 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 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 ongoing phase III trial for FDA approval 28 Biosynthesis editMain 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 subspecies cesius ATCC 27952 was initially found to be capable of producing the more widely used doxorubicin 30 This strain was created by Arcamone et al in 1969 by mutating a strain producing daunorubicin but not DXR at least in detectable quantities 31 Subsequently Hutchinson s group showed that under special environmental conditions or by the introduction of genetic modifications other strains of Streptomyces can produce doxorubicin 32 His group 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 33 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 34 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 30 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 35 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 36 Since daunorubicin is produced by fermentation it would be ideal if the bacteria could complete DXR synthesis more effectively Mechanism of action edit nbsp Diagram of two doxorubicin molecules intercalating DNA from PDB 1D12 37 Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis 11 38 39 This inhibits the progression of topoisomerase II an enzyme which relaxes supercoils in DNA for transcription 40 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 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 37 41 By intercalation doxorubicin can also induce histone eviction from transcriptionally active chromatin 42 43 As a result the DNA damage response epigenome and transcriptome are deregulated in doxorubicin exposed cells 42 History edit nbsp Bacteria producing doxorubicin were originally discovered in soil near Castel del Monte Apulia See also Anthracycline History Daunorubicin History and History of cancer chemotherapy 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 the Castel del Monte a 13th century castle A new strain of Streptomyces 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 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 44 45 46 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 47 Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound A strain of Streptomyces 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 31 Doxorubicin showed better activity than daunorubicin against mouse tumors and especially solid tumors It also showed a higher therapeutic index yet the cardiotoxicity remained 48 Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines 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 the National Cancer Institute NCI 44 In 2016 GPX 150 was granted orphan drug designation by US FDA 49 Society and culture editLegal status edit On 24 March 2022 the Committee for Medicinal Products for Human Use CHMP of the European 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 50 The applicant for this medicinal product is Accord Healthcare S L U 50 Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin 50 It contains the same active substance as Adriamycin but is available in a pegylated liposomal formulation 50 Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022 3 51 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 52 The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH 52 Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979 52 Celdoxome pegylated liposomal contains the same active substance as Adriamycin but is available in a pegylated liposomal formulation 52 Celdoxome pegylated liposomal was approved for medical use in the European Union in September 2022 4 Names edit It is also known as hydroxydaunorubicin and hydroxydaunomycin 53 It is sold under a number of different brand names including Adriamycin PFS Adriamycin RDF or Rubex 9 Formulations edit 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 in liposome 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 54 Research editCombination therapy experiments with sirolimus rapamycin and doxorubicin have shown promise in treating Akt positive lymphomas in mice 55 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 56 In 2006 animal research coupling a murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV 1 infection in mice 57 58 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 59 The pharmaceutical company GlaxoSmithKline GSK later identified doxorubicin in a set of compounds that inhibit parasite growth 60 Fluorescence edit 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 a theranostic 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 solvent dielectric 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 61 62 References edit a b c d Caelyx pegylated liposomal EPAR European Medicines Agency EPAR 17 September 2018 Archived from the original on 21 June 2022 Retrieved 20 June 2022 a b c d Myocet liposomal EPAR European Medicines Agency 17 September 2018 Archived from the original on 25 February 2022 Retrieved 20 June 2022 Text was copied from this source which is copyright European Medicines Agency Reproduction is authorized provided the source is acknowledged a b c Zolsketil pegylated liposomal EPAR European Medicines Agency EMA 24 January 2022 Archived from the original on 21 June 2022 Retrieved 20 June 2022 Text was copied from this source which is copyright European Medicines Agency Reproduction is authorized provided the source is acknowledged a b c Celdoxome pegylated liposomal EPAR European Medicines Agency EMA 20 June 2022 Retrieved 31 January 2023 Text was copied from this source which is copyright European Medicines Agency Reproduction is authorized provided the source is acknowledged Caelyx product information Health Canada 25 April 2012 Archived from the original on 21 June 2022 Retrieved 20 June 2022 Myocet product information Health Canada 25 April 2012 Retrieved 20 June 2022 Taro doxorubicin liposomal product information Health Canada 25 April 2012 Archived from the original on 14 May 2021 Retrieved 20 June 2022 a b c doxorubicin dosing indications interactions adverse effects and more Medscape Reference WebMD Archived from the original on 16 April 2014 Retrieved 15 April 2014 a b c d e f Brayfield A ed 19 December 2013 Doxorubicin Martindale The Complete Drug Reference Pharmaceutical Press Archived from the original on 28 August 2021 Retrieved 15 April 2014 a b c d e f g h i Doxorubicin Hydrochloride The American Society of Health System Pharmacists Archived from the original on 11 October 2016 Retrieved 12 January 2017 a b c Tacar O Sriamornsak P Dass CR February 2013 Doxorubicin an update on anticancer molecular action toxicity and novel drug delivery systems The Journal of Pharmacy and Pharmacology 65 2 157 170 doi 10 1111 j 2042 7158 2012 01567 x PMID 23278683 S2CID 34737360 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO a b British national formulary BNF 69 69 ed British Medical Association 2015 p 583 ISBN 9780857111562 Ravina E 2011 The Evolution of Drug Discovery From Traditional Medicines to Modern Drugs John Wiley amp Sons p 291 ISBN 9783527326693 Archived from the original on 18 September 2017 a b Rossi S ed 2013 Australian Medicines Handbook 2013 ed Adelaide The Australian Medicines Handbook Unit Trust ISBN 978 0 9805790 9 3 Bailon Moscoso N Coronel Hidalgo J Duarte Casar R Guaman Ortiz LM Figueroa JG Romero Benavides JC November 2023 Exploring the Antioxidant Potential of Tragia volubilis L Mitigating Chemotherapeutic Effects of Doxorubicin on Tumor Cells Antioxidants 12 11 2003 doi 10 3390 antiox12112003 ISSN 2076 3921 PMC 10669231 PMID 38001856 a b DOXIL Product Information PDF Archived from the original PDF on 21 September 2007 Retrieved 19 April 2007 a b Chatterjee K Zhang J Honbo N Karliner JS January 2010 Doxorubicin cardiomyopathy Cardiology 115 2 155 162 doi 10 1159 000265166 PMC 2848530 PMID 20016174 a b c d Chatterjee K Zhang J Honbo N Karliner JS 2010 Doxorubicin cardiomyopathy Cardiology 115 2 155 162 doi 10 1159 000265166 PMC 2848530 PMID 20016174 Dexrazoxane Hydrochloride Monograph for Professionals Drugs com Drugs com American Society of Health System Pharmacists Archived from the original on 1 August 2018 Retrieved 1 August 2018 Kaczmarek A Brinkman BM Heyndrickx L Vandenabeele P Krysko DV March 2012 Severity of doxorubicin induced small intestinal mucositis is regulated by the TLR 2 and TLR 9 pathways The Journal of Pathology 226 4 598 608 doi 10 1002 path 3009 PMID 21960132 S2CID 206325412 permanent dead link Outpatient Oncology Drug Series Doxorubicin 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7258 93 90006 Y PMID 8022857 a b Frederick CA Williams LD Ughetto G van der Marel GA van Boom JH Rich A Wang AH March 1990 Structural comparison of anticancer drug DNA complexes adriamycin and daunomycin Biochemistry 29 10 2538 2549 doi 10 1021 bi00462a016 PMID 2334681 Crystal structure is available for download as a PDB Archived 14 January 2008 at the Wayback Machine file Fornari FA Randolph JK Yalowich JC Ritke MK Gewirtz DA April 1994 Interference by doxorubicin with DNA unwinding in MCF 7 breast tumor cells Molecular Pharmacology 45 4 649 656 PMID 8183243 Momparler RL Karon M Siegel SE Avila F August 1976 Effect of adriamycin on DNA RNA and protein synthesis in cell free systems and intact cells Cancer Research 36 8 2891 2895 PMID 1277199 Archived from the original on 5 February 2009 Pommier Y Leo E Zhang H Marchand C May 2010 DNA topoisomerases and their poisoning by anticancer and antibacterial drugs Chemistry amp Biology 17 5 421 433 doi 10 1016 j chembiol 2010 04 012 PMC 7316379 PMID 20534341 Pigram WJ Fuller W Hamilton LD January 1972 Stereochemistry of intercalation interaction of daunomycin with DNA Nature 235 53 17 19 doi 10 1038 newbio235017a0 PMID 4502404 a b Pang B Qiao X Janssen L Velds A Groothuis T Kerkhoven R et al 2013 Drug induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin Nature Communications 4 5 1908 Bibcode 2013NatCo 4 1908P doi 10 1038 ncomms2921 PMC 3674280 PMID 23715267 Pang B de Jong J Qiao X Wessels LF Neefjes J July 2015 Chemical profiling of the genome with anti cancer drugs defines target specificities Nature Chemical Biology 11 7 472 480 doi 10 1038 nchembio 1811 PMID 25961671 a b Weiss RB December 1992 The anthracyclines will we ever find a better doxorubicin Seminars in Oncology 19 6 670 686 PMID 1462166 Baruffa G 1966 Clinical trials in Plasmodium falciparum malaria with a long acting sulphonamide Transactions of the Royal Society of Tropical Medicine and Hygiene 60 2 222 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which is copyright European Medicines Agency Reproduction is authorized provided the source is acknowledged Zolsketil Product information Union Register of medicinal products Retrieved 3 March 2023 a b c d Celdoxome pegylated liposomal Pending EC decision European Medicines Agency EMA 22 July 2022 Archived from the original on 28 July 2022 Retrieved 30 July 2022 Text was copied from this source which is copyright European Medicines Agency Reproduction is authorized provided the source is acknowledged Doxorubicin MedlinePlus Drug Information medlineplus gov Archived from the original on 13 July 2020 Retrieved 12 July 2020 FDA approval of generic version of cancer drug Doxil is expected to help resolve shortage Press release U S Food and Drug Administration FDA 4 February 2013 Archived from the original on 28 February 2014 Retrieved 22 February 2014 Wendel HG De Stanchina E Fridman JS Malina A Ray S Kogan S et al March 2004 Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy Nature 428 6980 332 337 Bibcode 2004Natur 428 332W doi 10 1038 nature02369 PMID 15029198 S2CID 4426215 Saha T Mondal J Khiste S Lusic H Hu ZW Jayabalan R et al September 2021 Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer Nanophotonics 10 12 3063 3073 Bibcode 2021Nanop 10 142S doi 10 1515 nanoph 2021 0142 PMC 8478290 PMID 34589378 Johansson S Goldenberg DM Griffiths GL Wahren B Hinkula J October 2006 Elimination of HIV 1 infection by treatment with a doxorubicin conjugated anti envelope antibody AIDS 20 15 1911 1915 doi 10 1097 01 aids 0000247111 58961 60 PMID 16988511 S2CID 42286690 Mitsuyasu R May 2013 Curing HIV lessons from cancer therapy Current Opinion in HIV and AIDS 8 3 224 229 doi 10 1097 COH 0b013e32835ef0a1 PMC 3789644 PMID 23454863 Friedman R Caflisch A August 2009 Discovery of plasmepsin inhibitors by fragment based docking and consensus scoring ChemMedChem 4 8 1317 1326 doi 10 1002 cmdc 200900078 PMID 19472268 S2CID 14642593 Archived from the original on 5 January 2013 Retrieved 28 May 2010 Gamo FJ Sanz LM Vidal J de Cozar C Alvarez E Lavandera JL et al May 2010 Thousands of chemical starting points for antimalarial lead identification Nature 465 7296 305 310 Bibcode 2010Natur 465 305G doi 10 1038 nature09107 PMID 20485427 S2CID 1143258 Karukstis KK Thompson EH Whiles JA Rosenfeld RJ July 1998 Deciphering the fluorescence signature of daunomycin and doxorubicin Biophysical Chemistry 73 3 249 263 doi 10 1016 s0301 4622 98 00150 1 PMID 9700924 Mohan P Rapoport N December 2010 Doxorubicin as a molecular nanotheranostic agent effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound mediated intracellular delivery and nuclear trafficking Molecular Pharmaceutics 7 6 1959 1973 doi 10 1021 mp100269f PMC 2997862 PMID 20957997 External links edit nbsp Media related to Doxorubicin at Wikimedia Commons Doxorubicin Drug Information Portal U S National Library of Medicine Doxorubicin hydrochloride Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Doxorubicin amp oldid 1194930689, wikipedia, wiki, book, books, library,

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