Topotecan

Topotecan
Systematic (IUPAC) name
(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride
Clinical data
Trade names Hycamtin
AHFS/Drugs.com monograph
MedlinePlus a610007
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration		 Intravenous infusion, oral
Pharmacokinetic data
Bioavailability 31.4 % in humans
Protein binding 35%
Metabolism Hepatic
Biological half-life 2-3 hours
Excretion Renal
Identifiers
CAS Number 123948-87-8 N 119413-54-6 (hydrochloride)
ATC code L01XX17
PubChem CID 60700
IUPHAR/BPS 7101
DrugBank DB01030 YesY
ChemSpider 54705 YesY
UNII 7M7YKX2N15 YesY
KEGG D08618 YesY
ChEMBL CHEMBL84 YesY
Chemical data
Formula C23H23N3O5 •HCl
Molar mass 457.9 g/mol
 NYesY (what is this?)  (verify)

Topotecan (trade name Hycamtin) is a chemotherapeutic agent that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its hydrochloride salt to treat ovarian cancer, lung cancer, and 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.

Mechanism 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 in the topoisomerase-I clevage complex.[7] The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain in the DNA strand.[7] This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA strand.[7] It is when the replication-fork collides with the trapped topoisomerase-I that DNA damage occurs.[7] The unbroken DNA strand breaks and the Mammalian cells cannot efficiently repair these double strand breaks.[8] The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli.[9] This disruption prevents DNA replication, and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting in apoptosis.

Side effects

Generic versions

Two generic versions have been approved in EU, and in Nov 2010 the US FDA approved a generic version.[10][11]

References

  1. ↑ http://www.fda.gov/bbs/topics/NEWS/NEW00537.html
  2. ↑ http://www.cancer.gov/cancertopics/druginfo/fda-topotecan-hydrochloride
  3. ↑ http://www.fda.gov/CDER/Offices/OODP/whatsnew/topotecan.htm FDA
  4. ↑ http://onctalk.com/2007/12/18/oral-topotecan-fda-approved/
  5. ↑ http://www.drugs.com/newdrugs/gsk-receives-approval-hycamtin-topotecan-capsules-relapsed-small-cell-lung-cancer-671.html 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. 1 2 3 4 Pommier, Yves. "Topoisomerase I inhibitors: camptothecins and beyond". Nature Reviews Cancer 6 (10): 789–802. doi:10.1038/nrc1977.
  8. ↑ 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.
  9. ↑ Bertrand, Richard; Solary, Eric; O'Connor, Patrick; Kohn, Kurt W.; Pommier, Yves (1994-04-01). "Induction of a Common Pathway of Apoptosis by Staurosporine". Experimental Cell Research 211 (2): 314–321. doi:10.1006/excr.1994.1093.
  10. ↑ "FDA Rubber-Stamps APP Pharma’s Generic Topotecan for Small Cell Lung and Cervical Cancers". 30 Nov 2010.
  11. ↑ DNA Topoisomerases and Cancer, Yves Pommier Editor, Humana Press 2012

[1] [2] [3]

External links

  1. ↑ Aditi, Dagli and Charles A Williams. “Angelman Syndrome.” NCBI (16 June 2011) Web. 10 Feb. 2015.
  2. ↑ Bailus, Barbara and David Segal. “The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders.” BMC Neuroscience 15.76 (2014). Web. 26 Jan. 2015.
  3. ↑ Beaudet, Arther L. “Angelman Syndrome: Drugs to awaken a paternal gene.” Nature. 481 (12 Jan. 2012): 150-152. Web. 10 Feb. 2015.
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