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Identification
Name Topotecan
Accession Number DB01030 (APRD00687)
Type small molecule
Groups approved
Description

An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I. [PubChem]

Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • topotecan
  • Topotecan Hcl
  • Topotecan Hydrochloride
  • Topotecan Lactone
  • Topotecane [INN-French]
  • Topotecanum [INN-Latin]
  • TPT
  • TTC
Brand names
  • Hycamptamine
  • Hycamptin
  • Hycamtin
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Enzyme Inhibitors
CAS number 119413-54-6
Weight Average: 421.4458
Monoisotopic: 421.163770861
Chemical Formula C23H23N3O5
InChI Key InChIKey=UCFGDBYHRUNTLO-QHCPKHFHSA-N
InChI
InChI=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
Plain Text
IUPAC Name
(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
SMILES
CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=CC4=C(C=CC(O)=C4CN(C)C)N=C13)C2=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Camptothecins
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Pyrans
  • Acetates
  • Phenols and Derivatives
  • Lactones
  • Pyridines and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Bipyridines
  • Hydroxyquinolines
  • Camptothecins
  • Aliphatic and Aryl Amines
  • Alcohols and Polyols
  • Pyridines
  • Heterocyclic compounds
  • Aromatic compounds
  • (Iso)quinolines and Derivatives
  • Imines
  • Phenyl Esters
Pharmacology
Indication For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.
Pharmacodynamics Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.
Mechanism of action Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.
Absorption Not Available
Volume of distribution Not Available
Protein binding 35%
Metabolism

Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.

Route of elimination Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.
Half life 2-3 hours
Clearance Not Available
Toxicity The primary anticipated complication of overdosage would consist of bone marrow suppression.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
  • Glaxosmithkline
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Hycamtin 4 mg vial 1306.1 USD vial
Hycamtin 1 mg capsule 358.92 USD capsule
Hycamtin 0.25 mg capsule 89.73 USD capsule
Patents
Country Patent Number Approved Expires
United States 5674872 1995-04-07 2015-04-07
United States 5004758 1993-05-28 2010-05-28
Canada 2103708 2004-04-27 2012-02-07
Canada 2103707 2003-12-09 2012-02-07
Properties
State solid
Melting point 213-218 oC
Experimental Properties
Property Value Source
water solubility 1 mg/ml PhysProp
logP 0.8 PhysProp
Predicted Properties
Property Value Source
water solubility 8.61e-01 g/l ALOGPS
logP 1.84 ALOGPS
logP -0.55 ChemAxon Molconvert
logS -2.69 ALOGPS
pKa 11.72 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 103.20 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 115.02 ChemAxon Molconvert
polarizability 44.86 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan – A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. Pubmed
  2. Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. Pubmed
  3. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. Pubmed
External Links
Resource Link
KEGG Compound C11158 Link_out
PubChem Compound 60700 Link_out
PubChem Substance 46505204 Link_out
ChemSpider 54705 Link_out
Therapeutic Targets Database DAP000648 Link_out
PharmGKB PA451729 Link_out
HET TTC Link_out
Drug Product Database 2231116 Link_out
RxList http://www.rxlist.com/cgi/generic2/topotec.htm Link_out
Drugs.com http://www.drugs.com/cdi/topotecan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Topotecan Link_out
ATC Codes
  • L01XX17
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (78.6 KB)
MSDS show (29.3 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. DNA topoisomerase 1

Pharmacological action: yes
Actions: inhibitor

The reaction catalyzed by topoisomerases leads to the conversion of one topological isomer of DNA to another

Organism class: human
UniProt ID: P11387 Link_out
Gene: TOP1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schmidt F, Rieger J, Wischhusen J, Naumann U, Weller M: Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage. Eur J Pharmacol. 2001 Jan 19;412(1):21-5. Pubmed
  2. strel’tsov SA, Mikheikin AL, Nechipurenko IuD: [Interaction of topotecan—a DNA topoisomerase I inhibitor—with dual-stranded polydeoxyribonucleotides. II. Formation of a complex containing several DNA molecules in the presence of topotecan] Mol Biol (Mosk). 2001 May-Jun;35(3):442-50. Pubmed
  3. Streltsov SA: Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I. J Biomol Struct Dyn. 2002 Dec;20(3):447-54. Pubmed
  4. Zhang J, Pu SP, Zhou YJ: [Preliminary study of apoptosis of human hepatocarcinoma cell line HepG2 induced by topotecan] Ai Zheng. 2002 Dec;21(12):1305-9. Pubmed
  5. Aisner J, Musanti R, Beers S, Smith S, Locsin S, Rubin EH: Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial. Clin Cancer Res. 2003 Jul;9(7):2504-9. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan – A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. Pubmed
  8. Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. Pubmed
  9. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. Pubmed

2. DNA topoisomerase I, mitochondrial

Pharmacological action: unknown
Actions: inhibitor

Relieves DNA strain that arise during duplication of mitochondrial DNA

Organism class: human
UniProt ID: Q969P6 Link_out
Gene: TOP1MT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kosovsky MJ, Soslau G: Immunological identification of human platelet mitochondrial DNA topoisomerase I. Biochim Biophys Acta. 1993 Jun 24;1164(1):101-7. Pubmed

3. DNA

Pharmacological action: yes
Actions: intercalation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

References:
  1. Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L: The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. Pubmed
  2. Pourquier P, Takebayashi Y, Urasaki Y, Gioffre C, Kohlhagen G, Pommier Y: Induction of topoisomerase I cleavage complexes by 1-beta -D-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1885-90. Pubmed

Enzymes

1. Cytochrome P450 3A4

Actions: inhibitor, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Transporters

1. ATP-binding cassette sub-family G member 2

Actions: substrate, inhibitor

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P: Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004 Apr 1;64(7):2333-7. Pubmed
  2. Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, Pluim D, Beijnen JH, Schellens JH: Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res. 2001 Apr;7(4):935-41. Pubmed
  3. Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T: Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2003 Jan;2(1):105-12. Pubmed
  4. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999 Sep 15;59(18):4559-63. Pubmed
  5. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6. Pubmed
  6. Allen JD, Van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH: Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 2003 Mar 15;63(6):1339-44. Pubmed
  7. Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11. Pubmed
  8. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010 Jun 1;70(11):4499-508. Epub 2010 May 11. Pubmed
  9. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. Epub 2009 Jun 30. Pubmed
  10. Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E: The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun. 2000 Apr 29;271(1):42-6. Pubmed
  11. Ishii M, Iwahana M, Mitsui I, Minami M, Imagawa S, Tohgo A, Ejima A: Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6. Anticancer Drugs. 2000 Jun;11(5):353-62. Pubmed
  12. Yang CH, Schneider E, Kuo ML, Volk EL, Rocchi E, Chen YC: BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem Pharmacol. 2000 Sep 15;60(6):831-7. Pubmed

2. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004 May;21(5):819-26. Pubmed
  2. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010 Jun 1;70(11):4499-508. Epub 2010 May 11. Pubmed
  3. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. Epub 2009 Jun 30. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on January 20, 2011 08:16

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.