Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Dactinomycin: Difference between pages

{{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 D.png

| width =

| image2 = Actinomycin D sticks.png

| 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 = [[Intravenous therapy|IV]]

| bioavailability =

| protein_bound = 5%

| metabolism = hepatic

| 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>

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 50-76-0

| ATC_prefix = L01

| ATC_suffix = DA01

| ATC_supplemental =

| PubChem = 2019

| 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

| 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 = Actinomycin D<br/><small>2-Amino- 4,6-dimethyl- 3-oxo- 3H-phenoxazine- 1,9-dicarboxylic acid bis- [(5,12-diisopropyl- 9,13,16-trimethyl- 4,7,11,14,17-pentaoxo- hexadecahydro- 10-oxa- 3a,6,13,16-tetraaza- cyclopentacyclohexadecen- 8-yl)- amide]</small>

<!-- 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 [[intravenous|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 [[necrosis|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=9780857111562|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 [[WHO Model List of Essential Medicines|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) |vauthors=((World Health Organization)) |publisher=World Health Organization |year=2023 |location=Geneva |hdl=10665/371090 |id=WHO/MHP/HPS/EML/2023.02 |author-link=World Health Organization |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 [[radiotherapy|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=9780323476744 |s2cid=198317393 }}</ref> since it can increase the [[radiosensitivity]] of [[Neoplasm|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 (medical)|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 (genetics)|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 [[fluorescence|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 [[paralog]]s identified between the two clusters.<ref name="Keller_2010" />

[[Image:Actinomycin D Biosynthesis.svg|center|thumb|420px|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 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Dactinomycin }}

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