Open Access Articles- Top Results for Topotecan


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Topotecan (trade name Hycamtin) is a chemotherapeutic agent that is a topoisomerase inhibitor. It is a water-soluble derivative of camptothecin. It is used in form of the hydrochloride to treat ovarian cancer and lung cancer, as well as other cancer types.

After GlaxoSmithKline received final FDA approval for Hycamtin Capsules on October 15, 2007, topotecan is the first topoisomerase I inhibitor for oral use.

Indications (approved uses)

Experimental use

Angelman’s syndrome is a neuro-genetic disorder characterized by severe developmental delays, seizures, speech impairments, and physical impairments. Angelman’s syndrome is an epigenetic disease and current treatments focus on symptoms. Angelman’s syndrome is caused by a deletion or mutation of the maternal allele for the ubiquitin protein ligase E3A (Huang et al). UBE3A is expressed in most tissues of the body, 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 leading to silencing of the paternal gene in neurons. The paternal UBE3A 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 (Beaudet). Treatment strategy for Angelman’s syndrome 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 (Malzac). Topotecan as a treatment for Angelman’s syndrome was described in Huang et al., 2011. 16 topoisomerasesinhibitors were found to unsilence the paternal UBE3A gene. Topoisomerases are enzymes that regulated the unwinding of DNA (Miller). Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A (Malpass). The enzymes bind to the DNA and cut the phosphate backbone, allowing the DNA to be unwound. Topotecan has been found to unsilence the UBE2A paternal allele by reducing the transcription of an antisense transcript. Topotecan inhibits topoisomerase I restoring UBE3A levels to wild-type range in cultured mince neurons (Huang). Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy (Beaudet). When tested on mice in vivo, topotecan was found to unsilence the paternal UBE3A gene in the hippocampus, striatum, and cerebral cortex but did not have a significant effect on the cerebellum unless a higher dose was administered (21.6 micrograms/hour for five days). The findings of the study on mice suggest the topoisomerase inhibitors have the potential to unsilence the paternal copy of the gene in humans to produce a normally functioning UBE3A protein. Currently, most symptoms due to Angelman’s syndrome are 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 (Aditi and Williams). These treatments only target the symptoms of Angelman’s and not the cause of the syndrome. This drug has already been administered to patients with cancer. Topotecan administered to patients with cancer has been well tolerated when administered to pediatric and adult patients and could be effective in treating Angelman’s(Huang). Topotecan if administered early on could prevent the symptoms that occur from the loss of UBE3A function in neurons.

Mode of action

Hycamtin or 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.[6] Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork. Topotecan intercalates between DNA bases. This intercalation disrupts the DNA duplication machinery when it reaches a site where topotecan is intercalated. This disruption prevents DNA replication, and ultimately leads to cell death. Mammalian cells cannot efficiently repair these double strand breaks.[7] This process leads to breaks in the DNA strand resulting in apoptosis.

Side effects

  • Myelosuppression
  • Diarrhea
  • Susceptibility to infection

Generic versions

Two generic versions have been approved in EU, and in Nov 2010 the US FDA approved a generic version.[8][9]


  1. ^
  2. ^
  3. ^ FDA
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  5. ^ Press release
  6. ^ Pommier, Y., Leo, E., Zhang, H., Marchand, C. 2010. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17: 421-433.
  7. ^ Staker, B.L. et al. (2002). "The mechanism of topoisomerase I poisoning by a camptothecin analog". PNAS 99 (24): 15387–15392. doi:10.1073/pnas.242259599. 
  8. ^ "FDA Rubber-Stamps APP Pharma’s Generic Topotecan for Small Cell Lung and Cervical Cancers". 30 Nov 2010. 
  9. ^ DNA Topoisomerases and Cancer, Yves Pommier Editor, Humana Press 2012

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External links

File:Topotecan Structural Formula V.1.svg
Systematic (IUPAC) name
quinoline-3,14(4H,12H)-dione monohydrochloride
Clinical data
Trade names Hycamtin
AHFS/ monograph
MedlinePlus a610007
  • AU: D
  • US: D (Evidence of risk)
Intravenous infusion, oral
Pharmacokinetic data
Bioavailability 31.4 % in humans [1][2]
Protein binding 35%
Metabolism Hepatic
Half-life 2-3 hours
Excretion Renal
123948-87-8 7pxN 119413-54-6 (hydrochloride)
PubChem CID 60700
DrugBank DB01030 7pxY
ChemSpider 54705 7pxY
UNII 7M7YKX2N15 7pxY
KEGG D08618 7pxY
Chemical data
Formula C23H23N3O5 •HCl</sub>

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