{{short description|Chemical compound}} {{cs1 config|name-list-style=vanc}}{{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 477241639 | IUPAC_name = 2-Amino-''N'',''{{prime|N}}''- bis[(6''S'',9''R'',10''S'',13''R'',18a''S'')-6,13-diisopropyl-2,5,9-trimethyl-1,4,7,11,14-pentaoxohexadecahydro-1''H''-pyrrolo[2,1-''i''][1,4,7,10,13]oxatetraazacyclohexadecin-10-yl]-4,6-dimethyl-3-oxo-3''H''-phenoxazine-1,9-dicarboxamide | image = Actinomycin C1.svg | image_class = skin-invert-image | width = | image2 = Actinomycin D sticks.png | image_class2 = bg-transparent <!--Clinical data--> | tradename = Cosmegen | Drugs.com = {{drugs.com|monograph|dactinomycin}} | MedlinePlus = a682224 | pregnancy_AU = D | pregnancy_US = D | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = IV <!--Pharmacokinetic data--> | bioavailability = | protein_bound = 5% | metabolism = hepatic | elimination_half-life = 36 hours | excretion = Bile<ref>{{cite book|vauthors = Kwok KK, Vincent EC, Gibson JN|title=Pharmacology and Therapeutics for Dentistry|date=2017|publisher=Mosby|pages=530–562|doi=10.1016/B978-0-323-39307-2.00036-9}}</ref> <!--Identifiers--> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 50-76-0 | ATC_prefix = L01 | ATC_suffix = DA01 | ATC_supplemental = | PubChem = 457193 | DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank = DB00970 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 10482167 | NIAID_ChemDB = 009885 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 1CC1JFE158 | KEGG_Ref = {{keggcite|changed|kegg}} | KEGG = C06770 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 27666 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1554 <!--Chemical data--> | C = 62 | H = 86 | N = 12 | O = 16 | smiles = Cc1c2oc3c(C)ccc(C(O)=N[C@@H]4C(O)=N[C@H](C(C)C)C(=O)N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)c3nc-2c(C(O)=N[C@@H]2C(O)=N[C@H](C(C)C)C(=O)N3CCC[C@H]3C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]2C)c(N)c1=O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C62H86N12O16/c1-27(2)42-59(84)73-23-17-19-36(73)57(82)69(13)25-38(75)71(15)48(29(5)6)61(86)88-33(11)44(55(80)65-42)67-53(78)35-22-21-31(9)51-46(35)64-47-40(41(63)50(77)32(10)52(47)90-51)54(79)68-45-34(12)89-62(87)49(30(7)8)72(16)39(76)26-70(14)58(83)37-20-18-24-74(37)60(85)43(28(3)4)66-56(45)81/h21-22,27-30,33-34,36-37,42-45,48-49H,17-20,23-26,63H2,1-16H3,(H,65,80)(H,66,81)(H,67,78)(H,68,79)/t33-,34-,36+,37+,42-,43-,44+,45+,48+,49+/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RJURFGZVJUQBHK-IIXSONLDSA-N | synonyms = {{ubl|Actinomycin C1|Actinomycin D|Actinomycin IV|Meractinomycin}} }}
<!-- Definition and medical uses --> '''Dactinomycin''', also known as '''actinomycin D''', is a chemotherapy medication used to treat a number of types of cancer.<ref name=AHFS2016/> This includes Wilms tumor, rhabdomyosarcoma, Ewing's sarcoma, trophoblastic neoplasm, testicular cancer, and certain types of ovarian cancer.<ref name=AHFS2016/> It is given by injection into a vein.<ref name=AHFS2016/>
<!-- Side effects and mechanism --> Most people develop side effects.<ref name=AHFS2016/> Common side effects include bone marrow suppression, vomiting, mouth ulcers, hair loss, liver problems, infections, and muscle pains.<ref name=AHFS2016/> Other serious side effects include future cancers, allergic reactions, and tissue death if extravasation occurs.<ref name=AHFS2016/> Use in pregnancy may harm the baby.<ref name=AHFS2016/> Dactinomycin is in the cytotoxic antibiotic family of medications.<ref name=BNF69>{{cite book|title=British national formulary: BNF 69|date=2015|publisher=British Medical Association|isbn=978-0-85711-156-2|page=582|edition=69}}</ref> It is believed to work by blocking the creation of RNA.<ref name=AHFS2016/>
<!-- History and culture --> Dactinomycin was approved for medical use in the United States in 1964.<ref name=AHFS2016>{{cite web|title=Dactinomycin|url=https://www.drugs.com/monograph/dactinomycin.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170911072431/https://www.drugs.com/monograph/dactinomycin.html|archive-date=11 September 2017}}</ref> It is on the 2023 World Health Organization's List of Essential Medicines.<ref name="WHO23rd">{{cite book |title=The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) |publisher=World Health Organization |year=2023 |location=Geneva |hdl=10665/371090 |id=WHO/MHP/HPS/EML/2023.02 |hdl-access=free}}</ref>
== Medical use == Actinomycin is a clear, yellowish liquid administered intravenously and most commonly used in treatment of a variety of cancers, including: *Gestational trophoblastic neoplasia<ref>{{cite journal | vauthors = Turan T, Karacay O, Tulunay G, Boran N, Koc S, Bozok S, Kose MF | title = Results with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) chemotherapy in gestational trophoblastic neoplasia | journal = International Journal of Gynecological Cancer | volume = 16 | issue = 3 | pages = 1432–1438 | year = 2006 | pmid = 16803542 | doi = 10.1111/j.1525-1438.2006.00606.x | s2cid = 32560653 }}</ref> *Wilms' tumor<ref>{{cite journal | vauthors = D'Angio GJ, Evans A, Breslow N, Beckwith B, Bishop H, Farewell V, Goodwin W, Leape L, Palmer N, Sinks L, Sutow W, Tefft M, Wolff J | display-authors = 6 | title = The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study | journal = Cancer | volume = 47 | issue = 9 | pages = 2302–2311 | date = May 1981 | pmid = 6164480 | doi = 10.1002/1097-0142(19810501)47:9<2302::aid-cncr2820470933>3.0.co;2-k | doi-access = free }}</ref> *Rhabdomyosarcoma<ref>{{cite journal | vauthors = Khatua S, Nair CN, Ghosh K | title = Immune-mediated thrombocytopenia following dactinomycin therapy in a child with alveolar rhabdomyosarcoma: the unresolved issues | journal = Journal of Pediatric Hematology/Oncology | volume = 26 | issue = 11 | pages = 777–779 | date = November 2004 | pmid = 15543019 | doi = 10.1097/00043426-200411000-00020 }}</ref> *Ewing's sarcoma<ref>{{cite journal | vauthors = Jaffe N, Paed D, Traggis D, Salian S, Cassady JR | title = Improved outlook for Ewing's sarcoma with combination chemotherapy (vincristine, actinomycin D and cyclophosphamide) and radiation therapy | journal = Cancer | volume = 38 | issue = 5 | pages = 1925–1930 | date = November 1976 | pmid = 991106 | doi = 10.1002/1097-0142(197611)38:5<1925::AID-CNCR2820380510>3.0.CO;2-J | doi-access = free }}</ref> *Malignant hydatidiform mole<ref>{{cite journal | vauthors = Uberti EM, Fajardo M, Ferreira SV, Pereira MV, Seger RC, Moreira MA, Torres MD, de Nápoli G, Schmid H | display-authors = 6 | title = Reproductive outcome after discharge of patients with high-risk hydatidiform mole with or without use of one bolus dose of actinomycin D, as prophylactic chemotherapy, during the uterine evacuation of molar pregnancy | journal = Gynecologic Oncology | volume = 115 | issue = 3 | pages = 476–481 | date = December 2009 | pmid = 19818481 | doi = 10.1016/j.ygyno.2009.09.012 }}</ref> Sometimes it will be combined with other drugs in chemotherapy regimens, like the VAC regimen (with vincristine and cyclophosphamide) for treating rhabdomyosarcoma and Ewing's sarcoma.<ref>{{Cite journal |display-authors=6 |vauthors=Arndt CA, Stoner JA, Hawkins DS, Rodeberg DA, Hayes-Jordan AA, Paidas CN, Parham DM, Teot LA, Wharam MD, Breneman JC, Donaldson SS, Anderson JR, Meyer WH |date=2009 |title=Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803 |journal=J Clin Oncol |volume=27 |issue=31 |pages=5182–5188 |doi=10.1200/JCO.2009.22.3768 |pmid=19770373|doi-access=free |pmc=2773476 }}</ref>
It is also used as a radiosensitizer in adjunct to radiotherapies,<ref>{{Cite book |title=Abeloff's Clinical Oncology |vauthors=Matthews NH, Moustafa F, Kaskas NM, Robinson-Bostom L, Pappas-Taffer L |publisher=Elsevier |year=2020 |pages=621–648 |chapter=41 - Dermatologic Toxicities of Anticancer Therapy |doi=10.1016/B978-0-323-47674-4.00041-4|isbn=978-0-323-47674-4 |s2cid=198317393 }}</ref> since it can increase the radiosensitivity of tumor cells by inhibiting repair of sublethal radiation damage and delay the onset of the compensatory hyperplasia that occurs following irradiation.<ref>{{cite journal | vauthors = Hagemann RF, Concannon JP | title = Mechanism of intestinal radiosensitization by actinomycin D | journal = The British Journal of Radiology | volume = 46 | issue = 544 | pages = 302–308 | date = April 1973 | pmid = 4720744 | doi = 10.1259/0007-1285-46-544-302 }}</ref>
== Side effects == Common adverse drug reaction includes bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhea. Actinomycin is a vesicant, if extravasation occurs.
==Mechanism== In cell biology, actinomycin D is shown to have the ability to inhibit transcription. Actinomycin D does this by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase.<ref>{{cite journal | vauthors = Sobell HM | title = Actinomycin and DNA transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 16 | pages = 5328–5331 | date = August 1985 | pmid = 2410919 | pmc = 390561 | doi = 10.1073/pnas.82.16.5328 | doi-access = free | bibcode = 1985PNAS...82.5328S }}</ref>
== History == Actinomycin D was the first antibiotic shown to have anti-cancer activity.<ref name="gen">{{cite journal| vauthors = Hollstein U |title=Actinomycin. Chemistry and mechanism of action|doi=10.1021/cr60292a002|journal=Chemical Reviews|volume=74|issue=6|pages=625–652|year=1974}}</ref> It was first isolated by Selman Waksman and his co-worker H. Boyd Woodruff in 1940,<ref>{{cite journal | vauthors = Waksman SA, Woodruff HB |s2cid=84774334|title=Bacteriostatic and bacteriocidal substances produced by soil actinomycetes|journal=Proceedings of the Society for Experimental Biology and Medicine |volume=45 |pages=609–614 |year=1940 |doi=10.3181/00379727-45-11768 }}</ref> using fermentation products from ''Streptomyces''.<ref>{{Cite book |title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet] |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |year=2012 |chapter=Dactinomycin |pmid=31644085}}</ref> It was approved by the U.S. Food and Drug Administration (FDA) on December 10, 1964,<ref>{{Cite web |title=Drugs@FDA: Dactinomycin |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=050682 |access-date=2023-10-15 |website=FDA}}</ref> and launched by Merck Sharp and Dohme under the trade name Cosmegen.
== Research use == Because actinomycin can bind DNA duplexes, it can also interfere with DNA replication, although other chemicals such as hydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.
Actinomycin D and its fluorescent derivative, 7-aminoactinomycin D (7-AAD), are used as stains in microscopy and flow cytometry applications. The affinity of these stains/compounds for GC-rich regions of DNA strands makes them excellent markers for DNA. 7-AAD binds to single stranded DNA; therefore it is a useful tool in determining apoptosis and distinguishing between dead cells and live ones.<ref>{{cite journal | vauthors = Toba K, Koike T, Watanabe K, Fuse I, Takahashi M, Hashimoto S, Takahashi H, Abe T, Yano T, Shibazaki Y, Itoh H, Aizawa Y | display-authors = 6 | title = Cell kinetic study of normal human bone marrow hematopoiesis and acute leukemia using 7AAD/PY | journal = European Journal of Haematology | volume = 64 | issue = 1 | pages = 10–21 | date = January 2000 | pmid = 10680701 | doi = 10.1034/j.1600-0609.2000.09005.x | s2cid = 41065740 }}</ref>
== Biosynthesis == Actinomycin D is composed of a central phenoxazinone chromophore tethered to two identical cyclic peptides and was first structurally characterized by Nuclear Magnetic Resonance (NMR) analysis in 1982.<ref name="Shafer_1982">{{cite journal | vauthors = Shafer RH, Formica JV, Delfini C, Brown SC, Mirau PA | title = Biosynthesis and characterization of [15N]actinomycin D and conformational analysis by nitrogen-15 nuclear magnetic resonance | journal = Biochemistry | volume = 21 | issue = 25 | pages = 6496–6503 | date = December 1982 | pmid = 6129895 | doi = 10.1021/bi00268a027 }}</ref> The biosynthesis of Actinomycin D has been under investigation since its discovery; early fermentation feeding experiments revealed the roles of both tryptophan and D-glutamate as precursor substrates,<ref>{{cite journal | vauthors = Sivak A, Katz E | title = Biosynthesis of the actinomycin chromophore. Influence of alpha-, 4-, 5-, and 6-methyl-DL-tryptophan on actinomycin synthesis | journal = Biochimica et Biophysica Acta | volume = 62 | issue = 1 | pages = 80–90 | date = July 1962 | pmid = 13913519 | doi = 10.1016/0006-3002(62)90493-6 }}</ref><ref name="Shafer_1982" /> and strain mutagenesis experiments demonstrated that a phenoxazinone synthase enzyme might be responsible for coupling of two moieties of 4-methyl-3-hydroxyanthranilic acid (4-MHA) into the final phenoxazinone structure.<ref>{{cite journal | vauthors = Troost T, Katz E | title = Phenoxazinone biosynthesis: accumulation of a precursor, 4-methyl-3-hydroxyanthranilic acid, by mutants of Streptomyces parvulus | journal = Journal of General Microbiology | volume = 111 | issue = 1 | pages = 121–132 | date = March 1979 | pmid = 458423 | doi = 10.1099/00221287-111-1-121 | doi-access = free }}</ref> The 4-MHA substrate was shown to be produced from tryptophan through the action of enzymes such as tryptophan dioxygenase, kynurenine formamidase, kynurenine hydroxylase, hydroxykynurenase, and methyltransferase.<ref>{{cite journal | vauthors = Jones GH | title = Actinomycin synthesis in Streptomyces antibioticus: enzymatic conversion of 3-hydroxyanthranilic acid to 4-methyl-3-hydroxyanthranilic acid | journal = Journal of Bacteriology | volume = 169 | issue = 12 | pages = 5575–5578 | date = December 1987 | pmid = 2445729 | pmc = 213988 | doi = 10.1128/jb.169.12.5575-5578.1987 }}</ref><ref name="Keller_2010">{{cite journal | vauthors = Keller U, Lang M, Crnovcic I, Pfennig F, Schauwecker F | title = The actinomycin biosynthetic gene cluster of ''Streptomyces chrysomallus'': a genetic hall of mirrors for synthesis of a molecule with mirror symmetry | journal = Journal of Bacteriology | volume = 192 | issue = 10 | pages = 2583–2595 | date = May 2010 | pmid = 20304989 | pmc = 2863554 | doi = 10.1128/JB.01526-09 }}</ref>
Early experiments elucidated the presence of non-ribosomal peptide synthetases,<ref name="Construction and in vitro analysis">{{cite journal | vauthors = Schauwecker F, Pfennig F, Grammel N, Keller U | title = Construction and in vitro analysis of a new bi-modular polypeptide synthetase for synthesis of N-methylated acyl peptides | journal = Chemistry & Biology | volume = 7 | issue = 4 | pages = 287–297 | date = April 2000 | pmid = 10780924 | doi = 10.1016/s1074-5521(00)00103-4 | doi-access = free }}</ref><ref name="Molecular cloning of the actinomyci">{{cite journal | vauthors = Schauwecker F, Pfennig F, Schröder W, Keller U | title = Molecular cloning of the actinomycin synthetase gene cluster from ''Streptomyces chrysomallus'' and functional heterologous expression of the gene encoding actinomycin synthetase II | journal = Journal of Bacteriology | volume = 180 | issue = 9 | pages = 2468–2474 | date = May 1998 | pmid = 9573200 | doi = 10.1128/jb.180.9.2468-2474.1998 | pmc = 107190 }}</ref><ref>{{cite journal | vauthors = Stindl A, Keller U | title = The initiation of peptide formation in the biosynthesis of actinomycin | journal = The Journal of Biological Chemistry | volume = 268 | issue = 14 | pages = 10612–10620 | date = May 1993 | doi = 10.1016/S0021-9258(18)82242-6 | pmid = 7683683 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Stindl A, Keller U | title = Epimerization of the D-valine portion in the biosynthesis of actinomycin D | journal = Biochemistry | volume = 33 | issue = 31 | pages = 9358–9364 | date = August 1994 | pmid = 8049237 | doi = 10.1021/bi00197a041 }}</ref> and subsequent purification and heterologous expression experiments<ref name="Construction and in vitro analysis"/><ref name="Molecular cloning of the actinomyci"/><ref>{{cite journal | vauthors = Keller U | title = Actinomycin synthetases. Multifunctional enzymes responsible for the synthesis of the peptide chains of actinomycin | journal = The Journal of Biological Chemistry | volume = 262 | issue = 12 | pages = 5852–5856 | date = April 1987 | pmid = 3571237 | doi = 10.1016/s0021-9258(18)45652-9 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Keller U | title = Acyl pentapeptide lactone synthesis in actinomycin-producing streptomycetes by feeding with structural analogs of 4-methyl-3-hydroxyanthranilic acid | journal = The Journal of Biological Chemistry | volume = 259 | issue = 13 | pages = 8226–8231 | date = July 1984 | pmid = 6203903 | doi = 10.1016/s0021-9258(17)39717-x | doi-access = free }}</ref> showed the ''acmD'' and ''acmA'' genes to be responsible for activation of the 4-MHA, which then undergoes chain elongation through the action of the ''acmB'' and ''acmC'' genes. In total, the NRPS assembly line is composed of twenty-two modules, including two each of epimerase and methylase domains.<ref>{{cite journal | vauthors = Pfennig F, Schauwecker F, Keller U | title = Molecular characterization of the genes of actinomycin synthetase I and of a 4-methyl-3-hydroxyanthranilic acid carrier protein involved in the assembly of the acylpeptide chain of actinomycin in Streptomyces | journal = The Journal of Biological Chemistry | volume = 274 | issue = 18 | pages = 12508–12516 | date = April 1999 | pmid = 10212227 | doi = 10.1074/jbc.274.18.12508 | doi-access = free }}</ref><ref name="Keller_2010" /> Recent sequencing of the actinomycin D gene cluster in ''Streptomyces chrysomallus'' showed that the four NRPS genes were surrounded on both sides by the two clusters of the genes involved in the well-studied kynurenine pathway and responsible for the production of 4-MHA from tryptophan, with nine paralogs identified between the two clusters.<ref name="Keller_2010" /> class=skin-invert-image|center|thumb|600px|Biosynthetic scheme of actinomycin D demonstrating the conversion of tryptophan to 4-MHA and the subsequent elongation by nonribosomal peptide synthetase assembly line genes. Figure modified from Keller et al., 2010.<ref name="Keller_2010" />
== References == {{reflist|32em}}
== External links == * {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/dactinomycin | archive-url = https://web.archive.org/web/20160705224919/http://druginfo.nlm.nih.gov/drugportal/name/Dactinomycin | archive-date = July 5, 2016 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Dactinomycin }}
{{Chemotherapeutic agents}}
{{portal bar|Medicine}}
Category:Polypeptide antibiotics Category:DNA replication inhibitors Category:Depsipeptides Category:Cyclic peptides Category:IARC Group 3 carcinogens Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate Category:DNA intercalaters