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Revision as of 13:45, 10 January 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 458637645 of page Topotecan for the Chem/Drugbox validation project (updated: 'DrugBank', 'CAS_number').  Latest revision as of 00:15, 27 August 2024 edit Whywhenwhohow (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers49,153 editsm script-assisted date audit and style fixes per MOS:NUM 
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{{Short description|Chemical compound}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use dmy dates|date=August 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 458636089 | verifiedrevid = 470611816
⚫ | IUPAC_name = (''S'')-10--4-ethyl-4,9-<br>dihydroxy-1''H''-pyranoindolizino<br>quinoline-3,14(4''H'',12''H'')-dione monohydrochloride
| image = Topotecan.svg | image = Topotecan.svg
| alt =


<!--Clinical data--> <!--Clinical data-->
| tradename = Hycamtin | tradename = Hycamtin, others
| Drugs.com = {{drugs.com|monograph|topotecan-hydrochloride}} | Drugs.com = {{drugs.com|monograph|topotecan-hydrochloride}}
| MedlinePlus = a610007 | MedlinePlus = a610007
| DailyMedID = Topotecan
| pregnancy_category = D <small>(], ])</small>
| pregnancy_AU = D
| legal_status = ℞-only <small>(U.S.)</small>, ] <small>(])</small>
| routes_of_administration = ], oral | routes_of_administration = ], ]
⚫ | ATC_prefix = L01
⚫ | ATC_suffix = CE01

| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Hycamtin- topotecan capsule | website=DailyMed | date=7 July 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa0815bb-8916-4c2c-9201-b04eb78e91fa | access-date=26 August 2024}}</ref><ref>{{cite web | title=Hycamtin- topotecan hydrochloride injection, powder, lyophilized, for solution | website=DailyMed | date=7 July 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeee060c-a9ec-423e-a374-8484009f8524 | access-date=26 August 2024}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Hycamtin EPAR | website=European Medicines Agency (EMA) | date=12 November 1996 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/hycamtin | access-date=26 August 2024}}</ref>


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = 31.4 % in humans<ref>{{cite journal | vauthors = Léger F, Loos WJ, Bugat R, Mathijssen RH, Goffinet M, Verweij J, Sparreboom A, Chatelut E | title = Mechanism-based models for topotecan-induced neutropenia | journal = Clinical Pharmacology and Therapeutics | volume = 76 | issue = 6 | pages = 567–78 | date = December 2004 | pmid = 15592328 | doi = 10.1016/j.clpt.2004.08.008 | s2cid = 37527965 }}</ref><ref>{{cite journal | vauthors = Gelderblom H, Loos WJ, Sissung TM, Burger H, Nooter K, Soepenberg O, Nortier JW, Verweij J, Figg WD, Sparreboom A | title = Effect of ABCG2 genotype and mRNA expression on the bioavailability of topotecan | journal = Journal of Clinical Oncology | date = July 2004 | volume = 22 | issue = 14 suppl | pages = 2015 | doi = 10.1200/jco.2004.22.90140.2015 | pmid = 28015603 }}</ref>
| bioavailability = 31.4 % in humans
| protein_bound = 35% | protein_bound = 35%
| metabolism = ] | metabolism = ]
| elimination_half-life = 2-3 hours | elimination_half-life = 2–3 hours
| excretion = ] | excretion = ]


<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 7101
| CAS_number_Ref = {{cascite|changed|??}} | CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 123948-87-8 --> | CAS_number = 123948-87-8
| CAS_supplemental = 119413-54-6 (hydrochloride) | CAS_supplemental = 119413-54-6 (hydrochloride)
⚫ | ATC_prefix = L01
⚫ | ATC_suffix = XX17
| PubChem = 60700 | PubChem = 60700
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01030 | DrugBank = DB01030
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08618 | KEGG = D08618
| KEGG2 = D02168
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 84 | ChEMBL = 84


<!--Chemical data--> <!--Chemical data-->
⚫ | IUPAC_name = (''S'')-10--4-ethyl-4,9-dihydroxy-1''H''-pyranoindolizinoquinoline-3,14(4''H'',12''H'')-dione monohydrochloride
| C=23 | H=23 | N=3 | O=5 </sub>•HCl | C=23 | H=23 | N=3 | O=5
| molecular_weight = 457.9 ]/]
| smiles = O=C\1N4\C(=C/C2=C/1COC(=O)2(O)CC)c3nc5c(cc3C4)c(c(O)cc5)CN(C)C | SMILES = O=C\1N4\C(=C/C2=C/1COC(=O)2(O)CC)c3nc5c(cc3C4)c(c(O)cc5)CN(C)C
| InChI = 1/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
| InChIKey = UCFGDBYHRUNTLO-QHCPKHFHBX
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1 | StdInChI = 1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
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| StdInChIKey = UCFGDBYHRUNTLO-QHCPKHFHSA-N | StdInChIKey = UCFGDBYHRUNTLO-QHCPKHFHSA-N
}} }}

'''Topotecan''', sold under the brand name '''Hycamtin''' among others, is a ] medication that is a ]. It is a synthetic, water-soluble ] of the natural chemical compound ]. It is used in the form of its ] ] to treat ], ] and other cancer types.

After ] received final ] approval for topotecan on 15 October 2007, it became the first topoisomerase I inhibitor for oral use.<ref>{{cite journal | vauthors = Delgado JL, Hsieh CM, Chan NL, Hiasa H | title = Topoisomerases as anticancer targets | journal = The Biochemical Journal | volume = 475 | issue = 2 | pages = 373–398 | date = January 2018 | pmid = 29363591 | pmc = 6110615 | doi = 10.1042/BCJ20160583 }}</ref>

==Uses==
* ] (FDA May 1996).<ref>{{cite web|url=https://www.fda.gov/bbs/topics/NEWS/NEW00537.html |title=FDA Approves Ovaerian Cancer Drug | work = U.S. Food and Drug Administration | date = 29 May 1996 |url-status=dead |archive-url=https://web.archive.org/web/20090119141150/https://www.fda.gov/bbs/topics/NEWS/NEW00537.html |archive-date=19 January 2009 }}</ref>
* ] (FDA June 2006).<ref>{{cite web|url=http://www.cancer.gov/cancertopics/druginfo/fda-topotecan-hydrochloride|title=FDA Approval for Topotecan Hydrochloride|work=National Cancer Institute|access-date=7 February 2009|archive-date=6 April 2015|archive-url=https://web.archive.org/web/20150406011800/http://www.cancer.gov/cancertopics/druginfo/fda-topotecan-hydrochloride|url-status=dead}}</ref><ref>{{cite web|url=https://www.fda.gov/CDER/Offices/OODP/whatsnew/topotecan.htm |title=FDA approves topotecan hydrochloride (hycamtin) in combination with cisplatin for the treatment of Stage IVB recurrent or persistent carcinoma of the cervix | work = FDA/Center for Drug Evaluation and Research |access-date=7 February 2009 |url-status=dead |archive-url=https://web.archive.org/web/20081107202948/https://www.fda.gov/cder/Offices/OODP/whatsnew/topotecan.htm |archive-date=7 November 2008 }}</ref>
* ] (SCLC) (FDA Oct 2007).<ref>{{cite web|url=http://onctalk.com/2007/12/18/oral-topotecan-fda-approved/ |title=Oral Topotecan FDA Approved in US for Second Line SCLC| work = Onc Talk |access-date=7 February 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090626080405/http://onctalk.com/2007/12/18/oral-topotecan-fda-approved/ |archive-date=26 June 2009 }}</ref><ref>{{cite web|url=https://www.drugs.com/newdrugs/gsk-receives-approval-hycamtin-topotecan-capsules-relapsed-small-cell-lung-carcinoma-671.html|title=GSK Receives Approval for Hycamtin (topotecan) Capsules for theTreatment of Relapsed Small Cell Lung Cancer}}</ref>

===Experimental uses===
As of 2016, experiments were under way for ], ], ] and ]. In addition, topotecan is experimentally treating ], ], ], ], ], and ].<ref>{{Cite journal| vauthors = Haglof K |year=2006|title=Recent developments in the clinical activity of topoisomerase-1 inhibitors|journal=Update on Cancer Therapeutics|volume=1|issue=2|pages=117–145|doi=10.1016/j.uct.2006.05.010}}</ref>

=== Angelman's syndrome ===
Angelman's syndrome is a neuro-genetic disorder characterized by severe developmental delays, seizures, speech impairments and physical impairments. It is an epigenetic disease and other treatments focus on symptoms. It is caused by a deletion or mutation of the maternal allele for the ] ] ] E3A.<ref name="Huang_2011" /> ] is expressed in most body tissues. However, in neurons only the maternal copy of the gene is expressed. UBE3A is located on ] and the paternal copy for the gene is genetically imprinted and is silenced by an ] transcript. The maternal copy control center of the gene is methylated, suppressing transcription in the antisense direction while the paternal copy control center is unmethylated.<ref name = "Beaudet_2011">{{cite journal | vauthors = Beaudet AL | title = Angelman syndrome: Drugs to awaken a paternal gene | journal = Nature | volume = 481 | issue = 7380 | pages = 150–2 | date = December 2011 | pmid = 22190038 | pmc = 3638729 | doi = 10.1038/nature10784 }}</ref>

Treatment involves unsilencing the paternal allele allowing the normal paternal UBE3A allele to be transcribed. UBE3A, in normal function, adds ubiquitin chains to proteins to target unnecessary or damaged proteins for degradation by the ].<ref name="pmid9585605">{{cite journal | vauthors = Malzac P, Webber H, Moncla A, Graham JM, Kukolich M, Williams C, Pagon RA, Ramsdell LA, Kishino T, Wagstaff J | title = Mutation analysis of UBE3A in Angelman syndrome patients | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1353–60 | date = June 1998 | pmid = 9585605 | pmc = 1377156 | doi = 10.1086/301877 }}</ref>

16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA.<ref>(Miller)</ref> Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.<ref name="pmid22270025">{{cite journal | vauthors = Malpass K | title = Neurodevelopmental disorders: Unsilencing dormant Ube3a--hope for Angelman syndrome? | journal = Nature Reviews. Neurology | volume = 8 | issue = 2 | pages = 62 | date = January 2012 | pmid = 22270025 | doi = 10.1038/nrneurol.2012.2 | s2cid = 858183 | doi-access = free }}</ref> The enzymes bind to the DNA and cut the phosphate backbone, allowing the DNA to be unwound. Topotecan unsilences the paternal UBE2A allele by reducing the transcription of an antisense transcript. Topotecan inhibits topoisomerase I restoring UBE3A levels to wild-type range in cultured mince neurons.<ref name="Huang_2011">{{cite journal | vauthors = Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, Sciaky N, Dutton JW, Lee HM, Chen X, Jin J, Bridges AS, Zylka MJ, Roth BL, Philpot BD|author14-link=Bryan Roth | title = Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons | journal = Nature | volume = 481 | issue = 7380 | pages = 185–9 | date = December 2011 | pmid = 22190039 | pmc = 3257422 | doi = 10.1038/nature10726 }}</ref>

Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy.<ref name = "Beaudet_2011" /> When tested on mice ''in vivo'', topotecan affected the ], ] and ] but not the ] unless a higher dose was administered (21.6 micrograms/hour for five days). The study suggested that the topoisomerase inhibitors have the potential to produce a normally functioning UBE3A protein. Most symptoms due to Angelman's syndrome are traditionally treated by ], ] and ]. ] is often prescribed as seizures are a common symptom of Angelman's syndrome.<ref>{{cite book | vauthors = Dagli AI, Mueller J, Williams CA | title = Angelman Syndrome | date = 1 January 1993 | pmid = 20301323 | url = https://www.ncbi.nlm.nih.gov/books/NBK1144/ | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A | publisher = University of Washington, Seattle }}</ref> These treatments target only symptoms.

This drug has been administered to cancer patients. It was well tolerated when administered to pediatric and adult patients.

==Mechanism of action==
Topotecan is a semi-synthetic derivative of ]. Camptothecin is a natural product extracted from the bark of the tree ]. Topoisomerase-I is a nuclear enzyme that relieves torsional strain in ] by opening single strand breaks.<ref>{{cite journal | vauthors = Pommier Y, Leo E, Zhang H, Marchand C | title = DNA topoisomerases and their poisoning by anticancer and antibacterial drugs | journal = Chemistry & Biology | volume = 17 | issue = 5 | pages = 421–33 | date = May 2010 | pmid = 20534341 | doi = 10.1016/j.chembiol.2010.04.012 | pmc = 7316379 | doi-access = free }}</ref> Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork. In physiological environments, topotecan is in equilibrium with its inactive carboxylate form.<ref name="Academic_Press_2003">{{Cite book|title=The Alkaloids: Chemistry and Biology |url=https://archive.org/details/isbn_0124695604 |url-access=limited |publisher=Academic Press|year=2003|isbn=978-0080521497| veditors = Cordell G |location=California|pages=–50}}</ref> Topotecan's active lactone form ] between DNA bases in the topoisomerase-I cleavage complex.<ref name="Pommier_2006">{{cite journal | vauthors = Pommier Y | title = Topoisomerase I inhibitors: camptothecins and beyond | journal = Nature Reviews. Cancer | volume = 6 | issue = 10 | pages = 789–802 | date = October 2006 | pmid = 16990856 | doi = 10.1038/nrc1977 | s2cid = 25135019 | url = https://zenodo.org/record/1233494 | doi-access = free }}</ref> The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain.<ref name="Pommier_2006" /> This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA.<ref name="Pommier_2006" /> When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs.<ref name="Pommier_2006" /> The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks.<ref>{{cite journal | vauthors = Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Stewart L | title = The mechanism of topoisomerase I poisoning by a camptothecin analog | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 24 | pages = 15387–92 | date = November 2002 | pmid = 12426403 | pmc = 137726 | doi = 10.1073/pnas.242259599 | bibcode = 2002PNAS...9915387S | doi-access = free }}</ref> The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli.<ref>{{cite journal | vauthors = Bertrand R, Solary E, O'Connor P, Kohn KW, Pommier Y | title = Induction of a common pathway of apoptosis by staurosporine | journal = Experimental Cell Research | volume = 211 | issue = 2 | pages = 314–21 | date = April 1994 | pmid = 8143779 | doi = 10.1006/excr.1994.1093 }}</ref> This disruption prevents DNA replication and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting in ]. Administration of topotecan down-regulates its target, topoisomerase-I; therefore, it is dosed to maximize efficacy and minimize related toxicity.<ref name="Academic_Press_2003" /> Topotecan is often given in combination with ] as first line treatment for extensive-stage ].<ref name="Academic_Press_2003" />

==Side effects==
* Myelosuppression, specifically neutropenia, leukopenia, anemia, and thrombocytopenia
* Diarrhea, nausea, vomiting, stomatitis, and constipation
* Increased susceptibility to infections
* Asthenia<ref name="Academic_Press_2003" />

==Generic versions==
Two generic versions have been approved in the European Union. In Nov 2010 the US FDA approved a generic version.<ref>{{cite news |url=http://www.genengnews.com/gen-news-highlights/fda-rubber-stamps-app-pharma-s-generic-topotecan-for-small-cell-lung-and-cervical-cancers/81244300/ |title=FDA Rubber-Stamps APP Pharma's Generic Topotecan for Small Cell Lung and Cervical Cancers |date=30 November 2010 |access-date=7 December 2010 |archive-date=30 June 2016 |archive-url=https://web.archive.org/web/20160630212849/http://www.genengnews.com/gen-news-highlights/fda-rubber-stamps-app-pharma-s-generic-topotecan-for-small-cell-lung-and-cervical-cancers/81244300/ |url-status=dead }}</ref><ref>{{cite book | veditors = Pommier Y |title=DNA topoisomerases and cancer |date=2012 |publisher=Humana Press |location=New York |isbn=978-1-4614-0322-7}}</ref>

== References ==
{{reflist|32em}}

== Sources ==
{{refbegin}}
* {{cite journal | vauthors = Bailus BJ, Segal DJ | title = The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders | journal = BMC Neuroscience | volume = 15 | pages = 76 | date = June 2014 | pmid = 24946931 | pmc = 4069279 | doi = 10.1186/1471-2202-15-76 | doi-access = free }}
{{refend}}

== External links ==
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