Doxorubicin

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Doxorubicin
Clinical data
Pronunciation/ˌdɒksəˈrbɪsɪn/
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
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
JSmol)
  • 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 checkY
 ☒NcheckY (what is this?)  (verify)

Doxorubicin, sold under the brand name Adriamycin among others, is a

together with other chemotherapy agents.[10] Doxorubicin is given by injection into a vein.[10]

Common side effects 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.

liposomes are also available; however, they are more expensive.[13] Doxorubicin was originally made from the bacterium Streptomyces peucetius.[14]

Medical uses

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

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

Side effects

Cardiotoxicity

The most dangerous side effect of doxorubicin is

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

Another common and potentially fatal complication of doxorubicin is

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

There is a

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

LVEF function, while still achieving superior tumor response. This finding is the basis for the ongoing phase III trial for FDA approval.[28]

Biosynthesis

Doxorubicin (DXR) is a 14-

hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic
pathway.

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

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 non

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​.[37]

Doxorubicin interacts with DNA by

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

Bacteria producing doxorubicin were originally discovered in soil near Castel del Monte, Apulia.

In the 1950s, an Italian research company,

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

Legal status

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

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

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

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.

murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV-1 infection in mice.[57][58]

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

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

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

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

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