Topotecan

• Ovarian cancer (FDA May 1996).{{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 }}
• Cervical cancer (FDA June 2006).{{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}}{{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 }}
• Small cell lung carcinoma (SCLC) (FDA Oct 2007).{{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 }}{{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}}

As of 2016, experiments were under way for Neuroblastoma, Brainstem glioma, Ewing's sarcoma and Angelman's syndrome. In addition, topotecan is experimentally treating Non-small cell lung cancer, Colorectal Cancer, Breast cancer, Non-Hodgkin Lymphoma, Endometrial cancer, and Oligodendroglioma.{{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}}

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 ubiquitin protein ligase E3A. UBE3A is expressed in most body tissues. However, in neurons only the maternal copy of the gene is expressed. UBE3A is located on chromosome 15 and the paternal copy for the gene is genetically imprinted and is silenced by an antisense RNA 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.{{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 }}

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 proteasome.{{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 }}

16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA.(Miller) Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.{{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 }} 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.{{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 }}

Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy. When tested on mice in vivo, topotecan affected the hippocampus, striatum and cerebral cortex but not the cerebellum 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 speech therapy, physical therapy and occupational therapy. Anti-seizure medication is often prescribed as seizures are a common symptom of Angelman's syndrome.{{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 }} These treatments target only symptoms.

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

Topotecan is a semi-synthetic derivative of camptothecin. Camptothecin is a natural product extracted from the bark of the tree Camptotheca acuminata. Topoisomerase-I is a nuclear enzyme that relieves torsional strain in DNA by opening single strand breaks.{{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 }} 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.{{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=[https://archive.org/details/isbn_0124695604/page/n5 1]–50}} Topotecan's active lactone form intercalates between DNA bases in the topoisomerase-I cleavage complex.{{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 }} The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain. This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA. When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs. The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks.{{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 }} The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli.{{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 }} This disruption prevents DNA replication and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting in apoptosis. Administration of topotecan down-regulates its target, topoisomerase-I; therefore, it is dosed to maximize efficacy and minimize related toxicity. Topotecan is often given in combination with paclitaxel as first line treatment for extensive-stage small-cell lung cancer.

• Myelosuppression, specifically neutropenia, leukopenia, anemia, and thrombocytopenia
• Diarrhea, nausea, vomiting, stomatitis, and constipation
• Increased susceptibility to infections
• Asthenia

Two generic versions have been approved in the European Union. In Nov 2010 the US FDA approved a generic version.{{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 }}{{cite book | veditors = Pommier Y |title=DNA topoisomerases and cancer |date=2012 |publisher=Humana Press |location=New York |isbn=978-1-4614-0322-7}}

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• {{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 }}

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• [https://www.cancer.gov/publications/dictionaries/cancer-drug/def/topotecan-hydrochloride NCI Drug Dictionary Definition of Topotecan]
• [https://www.cancer.gov/about-cancer/treatment/drugs/topotecanhydrochloride Topotecan Hydrochloride]

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Category:Lactams

Category:Delta-lactones

Category:Pyranoindolizinoquinolines

Category:Topoisomerase inhibitors

Category:Drugs developed by GSK plc

Category:Drugs developed by Novartis