Etoposide

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Etoposide
Etoposide.svg
Etoposide ball-and-stick.png
Clinical data
Pronunciation /ˌɛtoʊˈpoʊsaɪd/
Trade names Etopophos, Toposar, Vepesid, others
Other namesVP-16; VP-16-213
AHFS/Drugs.com Monograph
MedlinePlus a684055
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Highly variable, 25 to 75%
Protein binding 97%
Metabolism Liver (CYP3A4 involved)
Elimination half-life Oral: 6 h., IV: 6-12 h., IV in children: 3 h.
Excretion Kidney and fecal
Identifiers
  • 4'-Demethyl-epipodophyllotoxin 9-[4,6-O-(R)-ethylidene-beta-D-glucopyranoside], 4' -(dihydrogen phosphate)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.046.812 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C29H32O13
Molar mass 588.562 g·mol−1
3D model (JSmol)
Melting point 243.5 °C (470.3 °F)
  • C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)O[C@@H]3c4cc5c(cc4[C@H]([C@@H]6[C@@H]3COC6=O)c7cc(c(c(c7)OC)O)OC)OCO5)O)O
  • InChI=1S/C29H32O13/c1-11-36-9-20-27(40-11)24(31)25(32)29(41-20)42-26-14-7-17-16(38-10-39-17)6-13(14)21(22-15(26)8-37-28(22)33)12-4-18(34-2)23(30)19(5-12)35-3/h4-7,11,15,20-22,24-27,29-32H,8-10H2,1-3H3/t11-,15+,20-,21-,22+,24-,25-,26-,27-,29+/m1/s1 Yes check.svgY
  • Key:VJJPUSNTGOMMGY-MRVIYFEKSA-N Yes check.svgY
   (verify)

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. [2] It is also used for hemophagocytic lymphohistiocytosis. [3] It is used by mouth or injection into a vein. [2]

Contents

Side effects are very common. [2] They can include low blood cell counts, vomiting, loss of appetite, diarrhea, hair loss, and fever. [2] Other severe side effects include allergic reactions and low blood pressure. [2] [4] Use during pregnancy will likely harm the fetus. [2] Etoposide is in the topoisomerase inhibitor family of medication. [2] It is believed to work by damaging DNA. [2]

Etoposide was approved for medical use in the United States in 1983. [2] It is on the World Health Organization's List of Essential Medicines. [5]

Medical uses

Etoposide is used as a form of chemotherapy for cancers such as Kaposi’s sarcoma, Ewing's sarcoma, lung cancer, testicular cancer, lymphoma, nonlymphocytic leukemia, and glioblastoma multiforme. It is often given in combination with other drugs (such as bleomycin in treating testicular cancer). It is also sometimes used in a conditioning regimen prior to a bone marrow or blood stem cell transplant. [6]

Administration

It is given intravenously (IV) or orally in capsule or tablet form. If the drug is given IV, it must[ why? ] be done slowly over a 30- to 60-minute period[ according to whom? ] because it can lower blood pressure as it is being administered.[ citation needed ] Blood pressure is checked[ by whom? ] often[ when? ] during infusing, with the speed of administration adjusted[ by whom? ] accordingly.

Side effects

Common are:

Less common are:

When given with warfarin, it may cause bleeding. [7]

Pharmacology

Mechanism of action

Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme, which is an enzyme that aids in relaxing negative or positive supercoils in DNA. Topoisomerase II normally will form a double-stranded break in one DNA double-strand, allow another to pass through, and re-ligate the broken strands. Etoposide's binding prevents topoisomerase II from re-ligating the broken DNA strands, which causes the DNA breaks made by topoisomerase II to stay broken, and also prevents the topoisomerase II molecule from leaving the site and relieving tension elsewhere. This results in a double-strand break in the DNA that can have various deleterious effects on the cell, and depletion of topoisomerase II available to relieve further tension. [8] Cancer cells rely on this enzyme more than healthy cells, since they divide more rapidly. Therefore, this causes errors in DNA synthesis and promotes apoptosis of the cancer cell. [6] [9]

Chemistry

An illustration of the wild mandrake, showing part of the rhizome (at bottom) Podophyllum peltatum - Kohler-s Medizinal-Pflanzen-246.jpg
An illustration of the wild mandrake, showing part of the rhizome (at bottom)

Etoposide is a semisynthetic derivative of podophyllotoxin from the rhizome of the wild mandrake (Podophyllum peltatum). More specifically, it is a glycoside of podophyllotoxin with a D-glucose derivative. It is chemically similar to the anti-cancer drug teniposide, being distinguished only by a methyl group where teniposide has a thienyl. [10] Both these compounds have been developed with the aim of creating less toxic derivatives of podophyllotoxin. [11]

The substance is a white to yellow-brown, crystalline powder. It is soluble in organic solvents. [11]

It is used in form of its salt etoposide phosphate.

History

Etoposide was first synthesized in 1966 and U.S. Food and Drug Administration approval was granted in 1983. [6]

The nickname VP-16 likely comes from a compounding of the last name of one of the chemists who performed early work on the drug (von Wartburg) and podophyllotoxin. [12] Another scientist who was integral in the development of podophyllotoxin-based chemotherapeutics was the medical pharmacologist Hartmann F. Stähelin.

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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.

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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. 1 2 3 4 5 6 7 8 9 "Etoposide". The American Society of Health-System Pharmacists. Archived from the original on 31 March 2016. Retrieved 8 December 2016.
  3. ↑ Yildiz H, Van Den Neste E, Defour JP, Danse E, Yombi JC (January 2020). "Adult haemophagocytic lymphohistiocytosis: a Review". QJM. 115 (4): 205–213. doi: 10.1093/qjmed/hcaa011 . PMID   31943120.
  4. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 227. hdl: 10665/44053 . ISBN   9789241547659.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. 1 2 3 Hande KR (1998). "Etoposide: four decades of development of a topoisomerase II inhibitor". Eur. J. Cancer. 34 (10): 1514–21. doi:10.1016/S0959-8049(98)00228-7. PMID   9893622.
  7. ↑ Longe JL (2002). Gale Encyclopedia Of Cancer: A Guide To Cancer And Its Treatments . Detroit: Thomson Gale. pp.  397–399. ISBN   978-1-4144-0362-5.
  8. ↑ Pommier Y, Leo E, Zhang H, Marchand C (2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chem. Biol. 17 (5): 421–33. doi: 10.1016/j.chembiol.2010.04.012 . PMC   7316379 . PMID   20534341.
  9. ↑ Gordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA (2004). "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives". Toxicon. 44 (4): 441–59. doi:10.1016/j.toxicon.2004.05.008. PMID   15302526.
  10. ↑ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 894–5. ISBN   3-8047-1763-2.
  11. 1 2 Dinnendahl V, Fricke U, eds. (2015). Arzneistoff-Profile (in German). Vol. 4 (28th ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  12. ↑ Kuhn M, Von Wartburg A (1967). "Podophyllum-Lignane: Struktur und Absolutkonfiguration von Podorhizol-β-D-glucosid ( = Lignan F). 19. Mitt. über mitosehemmende Naturstoffe[1]". Helvetica Chimica Acta. 50 (6): 1546–65. doi:10.1002/hlca.19670500614. Archived from the original on 2013-01-05.
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