Topotecan

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Topotecan
Topotecan.svg
Clinical data
Trade names Hycamtin, Potactasol
AHFS/Drugs.com Monograph
MedlinePlus a610007
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Intravenous infusion, by mouth (capsules)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING [1] Rx-only
  • EU:Rx-only
Pharmacokinetic data
Bioavailability 31.4 % in humans [2] [3]
Protein binding 35%
Metabolism Liver
Elimination half-life 2–3 hours
Excretion Kidney
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.213.372 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H23N3O5
Molar mass 421.453 g·mol−1
3D model (JSmol)
  • O=C\1N4\C(=C/C2=C/1COC(=O)[C@]2(O)CC)c3nc5c(cc3C4)c(c(O)cc5)CN(C)C
  • 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 Yes check.svgY
  • Key:UCFGDBYHRUNTLO-QHCPKHFHSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Topotecan, sold under the brand name Hycamtin among others, is a chemotherapeutic agent medication 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.

Contents

After GlaxoSmithKline received final FDA approval for topotecan on October 15, 2007, it became the first topoisomerase I inhibitor for oral use. [4]

Uses

Experimental uses

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. [10]

Angelman's syndrome

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. [11] 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. [12]

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. [13]

16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA. [14] Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A. [15] 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. [16]

Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy. [12] 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. [17] These treatments target only symptoms.

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

Mechanism of action

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. [18] 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. [19] Topotecan's active lactone form intercalates between DNA bases in the topoisomerase-I cleavage complex. [20] The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain. [20] This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA. [20] When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs. [20] The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks. [21] The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli. [22] 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. [19] Topotecan is often given in combination with paclitaxel as first line treatment for extensive-stage small-cell lung cancer. [19]

Side effects

Generic versions

Two generic versions have been approved in the European Union. In Nov 2010 the US FDA approved a generic version. [23] [24]

Related Research Articles

DNA topoisomerases are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. A second topological challenge results from the linking or tangling of DNA during replication. Left unresolved, links between replicated DNA will impede cell division. The DNA topoisomerases prevent and correct these types of topological problems. They do this by binding to DNA and cutting the sugar-phosphate backbone of either one or both of the DNA strands. This transient break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

<span class="mw-page-title-main">Gemcitabine</span> Chemical compound

Gemcitabine, sold under the brand name Gemzar, among others, is a chemotherapy medication used to treat cancers. It is used to treat testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signaling.

<span class="mw-page-title-main">Etoposide</span> Chemotherapy medication

Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is also used for hemophagocytic lymphohistiocytosis. It is used by mouth or injection into a vein.

<span class="mw-page-title-main">Mitoxantrone</span> Chemical compound

Mitoxantrone is an anthracenedione antineoplastic agent.

<span class="mw-page-title-main">Irinotecan</span> Cancer medication

Irinotecan, sold under the brand name Camptosar among others, is a anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.

<span class="mw-page-title-main">UBE3A</span> Protein-coding gene in Homo sapiens

Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.

<span class="mw-page-title-main">Chromosome 15</span> Human chromosome

Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs and represents between 3% and 3.5% of the total DNA in cells. Chromosome 15 is an acrocentric chromosome, with a very small short arm, which contains few protein coding genes among its 19 million base pairs. It has a larger long arm that is gene rich, spanning about 83 million base pairs.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">Type I topoisomerase</span> Class of enzymes

In molecular biology Type I topoisomerases are enzymes that cut one of the two strands of double-stranded DNA, relax the strand, and reanneal the strand. They are further subdivided into two structurally and mechanistically distinct topoisomerases: type IA and type IB.

<span class="mw-page-title-main">KRAS</span> Protein-coding gene in humans

KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.

<span class="mw-page-title-main">Camptothecin</span> Chemical compound

Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata, a tree native to China used in traditional Chinese medicine. It has been used clinically more recently in China for the treatment of gastrointestinal tumors. CPT showed anticancer activity in preliminary clinical trials, especially against breast, ovarian, colon, lung, and stomach cancers. However, it has low solubility and adverse effects have been reported when used therapeutically, so synthetic and medicinal chemists have developed numerous syntheses of camptothecin and various derivatives to increase the benefits of the chemical, with good results. Four CPT analogues have been approved and are used in cancer chemotherapy today: topotecan, irinotecan, belotecan, and trastuzumab deruxtecan. Camptothecin has also been found in other plants including Chonemorpha fragrans.

<span class="mw-page-title-main">TOP1</span> DNA topoisomerase enzyme

DNA topoisomerase 1 is an enzyme that in humans is encoded by the TOP1 gene. It is a DNA topoisomerase, an enzyme that catalyzes the transient breaking and rejoining of a single strand of DNA.

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death, whereas a deficiency of only one of these genes does not. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differing phenotype, and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression.

<span class="mw-page-title-main">Belotecan</span> Chemical compound

Belotecan is a drug used in chemotherapy. It is a semi-synthetic camptothecin analogue indicated for small-cell lung cancer and ovarian cancer, approved in South Korea under the trade name Camtobell, presented in 2 mg vials for injection. The drug has been marketed by Chong Kun Dang Pharmaceuticals since 2003.

<span class="mw-page-title-main">PARP inhibitor</span> Pharmacological enzyme inhibitors of poly (ADP-ribose) polymerases

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).

<span class="mw-page-title-main">HU-331</span> Chemical compound

HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU-331 is a very specific inhibitor of topoisomerase II, compared with most known anticancer quinones. One of the main objectives of these studies is the development of a new quinone derived compound that produces anti-neoplastic activity while maintaining low toxicity at therapeutic doses.

<span class="mw-page-title-main">Ube3a-ATS</span> Non-coding RNA in the species Homo sapiens

UBE3A-ATS/Ube3a-ATS (human/mouse), otherwise known as ubiquitin ligase E3A-ATS, is the name for the antisense DNA strand that is transcribed as part of a larger transcript called LNCAT at the Ube3a locus. The Ube3a locus is imprinted and in the central nervous system expressed only from the maternal allele. Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of LNCAT, since non-coding antisense transcripts are often found at imprinted loci. The deletion and/or mutation of Ube3a on the maternal chromosome causes Angelman Syndrome (AS) and Ube3a-ATS may prove to be an important aspect in finding a therapy for this disease. While in patients with AS the maternal Ube3a allele is inactive, the paternal allele is intact but epigenetically silenced. If unsilenced, the paternal allele could be a source of active Ube3a protein in AS patients. Therefore, understanding the mechanisms of how Ube3a-ATS might be involved in silencing the paternal Ube3a may lead to new therapies for AS. This possibility has been demonstrated by a recent study where the drug topotecan, administered to mice suffering from AS, activated expression of the paternal Ube3a gene by lowering the transcription of Ube3a-ATS.

This is a historical timeline of the development and progress of cancer treatments, which includes time of discovery, progress, and approval of the treatments.

<span class="mw-page-title-main">Diflomotecan</span> Chemical compound

Diflomotecan is a chemotherapeutic agent that is a topoisomerase inhibitor (Top1). It varies from other camptothecin based Top1 inhibitors like topotecan in having a 7-membered E-ring. The oxepan-2-one ring in the homocamptothecin analogues is more stable in plasma compared to the 6-membered lactone in camptothecin. Diflomotecan was the first homocamptothecin to enter clinical trials and is currently in phase I for treating patients with sensitive small cell lung cancer (SCLC).

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. ↑ Léger F, Loos WJ, Bugat R, Mathijssen RH, Goffinet M, Verweij J, et al. (December 2004). "Mechanism-based models for topotecan-induced neutropenia". Clinical Pharmacology and Therapeutics. 76 (6): 567–78. doi:10.1016/j.clpt.2004.08.008. PMID   15592328. S2CID   37527965.
  3. ↑ Gelderblom H, Loos WJ, Sissung TM, Burger H, Nooter K, Soepenberg O, et al. (July 2004). "Effect of ABCG2 genotype and mRNA expression on the bioavailability of topotecan". Journal of Clinical Oncology. 22 (14 suppl): 2015. doi:10.1200/jco.2004.22.90140.2015. PMID   28015603.
  4. ↑ Delgado, Justine L.; Hsieh, Chao-Ming; Chan, Nei-Li; Hiasa, Hiroshi (2018-01-31). "Topoisomerases as anticancer targets". Biochemical Journal. 475 (2): 373–398. doi:10.1042/BCJ20160583. ISSN   0264-6021. PMC   6110615 . PMID   29363591.
  5. ↑ "FDA Approves Ovaerian Cancer Drug". U.S. Food and Drug Administration. 29 May 1996. Archived from the original on January 19, 2009.
  6. ↑ "FDA Approval for Topotecan Hydrochloride". National Cancer Institute. Archived from the original on 2015-04-06. Retrieved 2009-02-07.
  7. ↑ "FDA approves topotecan hydrochloride (hycamtin) in combination with cisplatin for the treatment of Stage IVB recurrent or persistent carcinoma of the cervix". FDA/Center for Drug Evaluation and Research. Archived from the original on November 7, 2008. Retrieved February 7, 2009.
  8. ↑ "Oral Topotecan FDA Approved in US for Second Line SCLC". Onc Talk. Archived from the original on June 26, 2009. Retrieved February 7, 2009.
  9. ↑ "GSK Receives Approval for Hycamtin (topotecan) Capsules for theTreatment of Relapsed Small Cell Lung Cancer".
  10. ↑ Haglof K (2006). "Recent developments in the clinical activity of topoisomerase-1 inhibitors". Update on Cancer Therapeutics. 1 (2): 117–145. doi:10.1016/j.uct.2006.05.010.
  11. ↑ (Huang et al)
  12. 1 2 Beaudet 2011.
  13. ↑ Malzac P, Webber H, Moncla A, Graham JM, Kukolich M, Williams C, Pagon RA, Ramsdell LA, Kishino T, Wagstaff J (June 1998). "Mutation analysis of UBE3A in Angelman syndrome patients". American Journal of Human Genetics. 62 (6): 1353–60. doi:10.1086/301877. PMC   1377156 . PMID   9585605.
  14. ↑ (Miller)
  15. ↑ Malpass K (January 2012). "Neurodevelopmental disorders: Unsilencing dormant Ube3a--hope for Angelman syndrome?". Nature Reviews. Neurology. 8 (2): 62. doi: 10.1038/nrneurol.2012.2 . PMID   22270025. S2CID   858183.
  16. ↑ 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 (December 2011). "Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons". Nature. 481 (7380): 185–9. doi:10.1038/nature10726. PMC   3257422 . PMID   22190039.
  17. ↑ (Aditi and Williams)
  18. ↑ Pommier Y, Leo E, Zhang H, Marchand C (May 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chemistry & Biology. 17 (5): 421–33. doi: 10.1016/j.chembiol.2010.04.012 . PMC   7316379 . PMID   20534341.
  19. 1 2 3 4 Cordell G, ed. (2003). The Alkaloids: Chemistry and Biology . California: Academic Press. pp.  1–50. ISBN   978-0080521497.
  20. 1 2 3 4 Pommier Y (October 2006). "Topoisomerase I inhibitors: camptothecins and beyond". Nature Reviews. Cancer. 6 (10): 789–802. doi: 10.1038/nrc1977 . PMID   16990856. S2CID   25135019.
  21. ↑ Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Stewart L (November 2002). "The mechanism of topoisomerase I poisoning by a camptothecin analog". Proceedings of the National Academy of Sciences of the United States of America. 99 (24): 15387–92. Bibcode:2002PNAS...9915387S. doi: 10.1073/pnas.242259599 . PMC   137726 . PMID   12426403.
  22. ↑ Bertrand R, Solary E, O'Connor P, Kohn KW, Pommier Y (April 1994). "Induction of a common pathway of apoptosis by staurosporine". Experimental Cell Research. 211 (2): 314–21. doi:10.1006/excr.1994.1093. PMID   8143779.
  23. ↑ "FDA Rubber-Stamps APP Pharma's Generic Topotecan for Small Cell Lung and Cervical Cancers". 30 Nov 2010. Archived from the original on 30 June 2016. Retrieved 7 December 2010.
  24. ↑ DNA Topoisomerases and Cancer, Yves Pommier Editor, Humana Press 2012

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