Doxorubicin

Doxorubicin
Clinical data
Pronunciation /ˌdɒksəˈruːbɪsɪn/
Trade names Adriamycin, Doxil, Caelyx, Myocet, others
AHFS/Drugs.com Monograph
MedlinePlus a682221
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration		 intravenous, intravesical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 5% (by mouth)
Protein binding 75%[1]
Metabolism Liver
Biological half-life Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1-3 hours[1][2]
Excretion Urine (5-12%), faeces (40-50%)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.041.344
Chemical and physical data
Formula C27H29NO11
Molar mass 543.52 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Doxorubicin, sold under the trade names Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein.[3]

Common side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth. 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. People often experience red discoloration of the urine for a few days. Doxorubicin is in the anthracycline and antitumor antibiotic family of medications.[3] It works in part by interfering with the function of DNA.[4]

Doxorubicin was approved for medical use in the United States in 1974.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] The wholesale cost in the developing world is about 3.88 to 32.79 USD per 50 mg vial.[6] In the United Kingdom this amount costs the NHS about £100.12.[7][8] Versions that are pegylated and in liposomes are also available; however, are more expensive.[8] Doxorubicin was originally made from the bacteria Streptomyces peucetius.[9]

Medical 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][10] 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).[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.[11]

Liposomal form

There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, sold as Doxil. 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 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 form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.[12][13]

A non-pegylated liposomal doxorubicin, called Myocet, is approved in Europe and Canada for treatment of metastatic breast cancer in combination with cyclophosphamide, but 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 hand-foot syndrome. 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.[12]

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.[14] 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.[14] 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.[15]

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.[11]

Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"[16] or "red death."[17]

Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.[18][19]

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.[20]

Biosynthesis

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.[21] This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities.[22] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of Streptomyces can produce doxorubicin.[23] 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.[24] 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.[25] 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.[21] 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.[26] 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.[27] Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.

Mechanism of action

Diagram of two doxorubicin molecules intercalating DNA, from PDB: 1D12​.[28]

Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.[4][29][30] This inhibits the progression of topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription.[31] 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.[4] It may also increase quinone type free radical production, hence contributing to its cytotoxicity.[10]

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.[28][32]

By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin.[33][34] As a result, DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.[33]

History

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.[35][36][37] 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 produce fatal cardiac toxicity.[38]

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.[22] Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.[39]

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).[35] In 2016 GPX-150 was granted orphan drug designation by US FDA.[40]

Society and culture

Names

It is also known as hydroxydaunorubicin and hydroxydaunomycin.

It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.[2]

Formulations

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.[2]

Shortage

As of February 2014, Doxil was available in limited supply.[41] 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.[42] The problems began when Ben Venue temporarily shut down their manufacturing facility due to quality control issues.[43]

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.[44] The agency said it intends to continue allowing the importation of Lipodox until Sun has made enough generic Doxil to meet demand.[45]

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.[46]

Research

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.[47]

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.[48]

Antimalarial activity

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.[49] The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth [50]

Fluorescence

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.[51][52]

References

  1. 1 2 3 "(doxorubicin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 15 April 2014.
  2. 1 2 3 4 5 6 Brayfield, A, ed. (19 December 2013). "Doxorubicin". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 15 April 2014.
  3. 1 2 3 "Doxorubicin Hydrochloride". The American Society of Health-System Pharmacists. Retrieved 12 January 2017.
  4. 1 2 3 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): 157–70. PMID 23278683. doi:10.1111/j.2042-7158.2012.01567.x.
  5. ↑ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
  6. ↑ "Doxorubicin HCL". International Drug Price Indicator Guide. Retrieved 8 December 2016.
  7. ↑ "Doxorubicin: British National Formulary". BNF. Archived from the original on 2012-08-30. Retrieved 6 March 2017.
  8. 1 2 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 583. ISBN 9780857111562.
  9. ↑ Ravina, Enrique (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 291. ISBN 9783527326693.
  10. 1 2 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  11. 1 2 "DOXIL Product Information Archived September 21, 2007, at the Wayback Machine.." Ortho Biotech Products, L.P. Retrieved on April 19, 2007.
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  13. ↑ "Doxorubicin liposomal". Chemocare. Cleveland Clinic. Retrieved 2009-11-27.
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  15. ↑ Kaczmarek A, Brinkman BM, Heyndrickx L, Vandenabeele P, Krysko DV J (2012). "Severity of doxorubicin-induced small intestinal mucositis is regulated by the TLR-2 and TLR-9 pathways.". J Pathol. 226 (4): 598–608. PMID 21960132. doi:10.1002/path.3009.
  16. ↑ Bloch, Richard; Bloch, Annette. "25 Most Asked Questions". Fighting Cancer. R. A. Bloch Cancer Foundation. Archived from the original on June 26, 2007. Retrieved 2007-06-28.
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  18. ↑ Yeo W, Lam KC, Zee B, et al. (November 2004). "Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy". Ann Oncol. 15 (11): 1661–6. PMID 15520068. doi:10.1093/annonc/mdh430.
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  20. ↑ http://www.nejm.org/image-challenge?ci=09012011&query=TOC
  21. 1 2 Lomovskaya N, Otten SL, Doi-Katayama Y, et al. (1999). "Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene". J. Bacteriol. 181 (1): 305–18. PMC 103563 Freely accessible. PMID 9864344.
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  28. 1 2 Frederick CA, Williams LD, Ughetto G, et al. (March 1990). "Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin". Biochemistry. 29 (10): 2538–49. PMID 2334681. doi:10.1021/bi00462a016. Crystal structure is available for download as a PDB file.
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  33. 1 2 Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van Tellingen O, Janssen J, Huijgens P, Zwart W, Neefjes J (2013). "Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin". Nature Communications. 4 (5): 1908. PMC 3674280 Freely accessible. PMID 23715267. doi:10.1038/ncomms2921.
  34. ↑ Pang B, de Jong J, Qiao X, Wessels LF, Neefjes J (2015). "Chemical profiling of the genome with anti-cancer drugs defines target specificities". Nature Chemical Biology. 11 (7): 472–80. PMID 25961671. doi:10.1038/nchembio.1811.
  35. 1 2 Weiss RB (December 1992). "The anthracyclines: will we ever find a better doxorubicin?". Seminars in Oncology. 19 (6): 670–86. PMID 1462166.
  36. ↑ Baruffa G (1966). "Clinical trials in Plasmodium falciparum malaria with a long-acting sulphonamide". Trans. R. Soc. Trop. Med. Hyg. 60: 222–4. PMID 5332105. doi:10.1016/0035-9203(66)90030-7.
  37. ↑ Per prior citation, the first publication: Camerino B, Palamidessi G (1960) Derivati della parazina II. Sulfonamdopir (in Italian). Gazz Chim Ital 90:1802–1815
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  40. ↑ Investigational Sarcoma Drug GPX-150 Gets Orphan Drug Designation. 2016
  41. ↑ "Drug Shortages, doxorubicin". US Food and Drug Administration. Retrieved 2014-02-22.
  42. ↑ Peter Loftus (2011-07-21). "J&J is Short of Cancer Drug Doxil". Wall Street Journal.
  43. ↑ "Ben Venue Laboratories – Voluntary Shutdown". US Food and Drug Administration. 2011-11-30. Retrieved 2014-02-22.
  44. ↑ Harris, Gardiner (2012-02-21). "Shipments From Abroad to Help Ease Shortage of Two Cancer Drugs". New York Times. Retrieved 2014-02-22.
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  48. ↑ Johansson S, Goldenberg D, Griffiths G, Wahren B, Hinkula J (2006). "Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody". AIDS. 20 (15): 1911–1915. PMID 16988511. doi:10.1097/01.aids.0000247111.58961.60.
  49. ↑ Friedman R, Caflisch A (2009). "Discovery of Plasmepsin Inhibitors by Fragment-Based Docking and Consensus Scoring". ChemMedChem. 4 (8): 1317–26. PMID 19472268. doi:10.1002/cmdc.200900078.
  50. ↑ Gamo F-J; et al. (2010). "Thousands of chemical starting points for antimalarial lead identification". Nature. 465 (7296): 305–310. PMID 20485427. doi:10.1038/nature09107.
  51. ↑ Karukstis K, Thompson E, Whiles J, Rosenfeld R (1998). "Deciphering the fluorescence signature of daunomycin and doxorubicin". Biophysical Chemistry. 73: 249–263. doi:10.1016/s0301-4622(98)00150-1.
  52. ↑ Mohan P, Rapoport N (2010). "Doxorubicin as a Molecular Nanotheranostic Agent: Effect of Doxorubicin Encapsulation in Micelles or Nanoemulsions on the Ultrasound-Mediated Intracellular Delivery and Nuclear Trafficking". Mol. Pharmaceutics. 7: 1959–1973. doi:10.1021/mp100269f.

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