Topotecan

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Topotecan
Topotecan Structural Formula V.1.svg
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 cat.
Legal status
Routes Intravenous infusion, oral
Pharmacokinetic data
Bioavailability 31.4 % in humans [1][2]
Protein binding 35%
Metabolism Hepatic
Half-life 2-3 hours
Excretion Renal
Identifiers
CAS number 123948-87-8 N 119413-54-6 (hydrochloride)
ATC code L01XX17
PubChem CID 60700
DrugBank DB01030
ChemSpider 54705 YesY
UNII 7M7YKX2N15 YesY
KEGG D08618 YesY
ChEMBL CHEMBL84 YesY
Chemical data
Formula C23H23N3O5 •HCl 
Mol. mass 457.9 g/mol
 N (what is this?)  (verify)

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)[edit]

Experimental use[edit]

Mode of action[edit]

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[edit]

  • Myelosuppression
  • Diarrhea
  • Susceptibility to infection

Generic versions[edit]

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

References[edit]

  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. ^ 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

External links[edit]