Medical use Edit

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.[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] Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged.[15] This results in both systolic and diastolic dysfunction.[15] Eventually, heart failure can result, which carries a 50% mortality rate.[15] There is no effective treatment against established cardiomyopathy caused by the drug as of 2010.[15] The drug dexrazoxane may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases.[16] Other Edit Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening infection of the bowel.[17] 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.[11] Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"[18][19] or "red death."[20] Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.[21][22] 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.[23]

Biosynthesis Edit

Mechanism of action Edit

[31] Diagram of two doxorubicin molecules intercalating DNA, from ​. Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.[4][32][33] This inhibits the progression of topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription.[34] 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.[31][35] By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin.[36][37] As a result, DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.[36]

History Edit

Society and culture Edit

Names Edit 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 Edit 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 Edit Before March 2014, Doxil was available in limited supply.[44] 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.[45] The problems began when Ben Venue temporarily shut down their manufacturing facility due to quality control issues.[46] 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.[47] The agency said it intends to continue allowing the importation of Lipodox until Sun has made enough generic Doxil to meet demand.[48] 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.[49]

Research Edit

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.[50] 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.[51] 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.[52] The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth [53] 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.[54][55]

See also Edit