Etoposid

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H350：Kann Krebs verursachen.

  H412：Schädlich für Wasserorganismen, mit langfristiger Wirkung.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

Etoposide Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R45:Kann Krebs erzeugen.
  R22:Gesundheitsschädlich beim Verschlucken.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.

• Beschreibung

  Etoposide is a plant alkaloid and an inhibitor of topoisomerase II (IC₅₀ = 60.3 μM). It inhibits proliferation of a variety of adenocarcinoma cells (IC₅₀s = 0.005-12,200 μM) and human umbilical vein endothelial (HUVEC) cells (IC₅₀ = 0.249 μM). It reduces tumor growth in an Ma human embryonal carcinoma mouse xenograft model when administered at a dose of 25 mg/kg, an effect that is enhanced by concomitant administration of the immunosuppressant cyclosporin A . Etoposide also inhibits nuclear receptor coactivator 3 (IC₅₀ = 2.48 μM). Formulations containing etoposide have been used in combination therapy in the treatment of cancer.

• Chemische Eigenschaften

  White or almost white, crystalline powder, slightly hygroscopic
  

• Originator

  Etopos,Lemery,Mexico

• Verwenden

  Etoposide is used for germinogenic tumors, ovarian, stomach, and lung cancer, Hodgkin’s disease, and non-Hodgkin’s lymphoma for both monotherapy and in combination therapy.

• Verwenden

  anticonvulsant

• Verwenden

  An antitumur agent that complexes with topoisomerase II and DNA to enhance double-strand and single strand cleavage of DNA and reversible inhitit religation. Blocks the cell cycle in S-phase and G2-phase of the cell cycle. Induces apoptosis in nor

• Verwenden

  A DNA topoisomerase II inhibitor. Semi-synthetic derivative of podophyllotoxin, related structurally to Teniposide. Antineoplastic.

• Definition

  ChEBI: Etoposide is a beta-D-glucoside, a furonaphthodioxole and an organic heterotetracyclic compound. It has a role as an antineoplastic agent and a DNA synthesis inhibitor. It is functionally related to a podophyllotoxin and a 4'-demethylepipodophyllotoxin.

• Indications

  Etoposide (VePesid) is a semisynthetic derivative of podophyllotoxin that is produced in the roots of the American mandrake, or May apple. Unlike podophyllotoxin and vinca alkaloids, etoposide does not bind to microtubules. It forms a complex with the enzyme topoisomerase II, which results in a single-strand breakage of DNA. It is most lethal to cells in the S- and G2-phases of the cell cycle. Drug resistance to etoposide is thought to be caused by decreased cellular drug accumulation.
  Etoposide is most useful against testicular and ovarian germ cell cancers, lymphomas, small cell lung cancers, and acute myelogenous and lymphoblastic leukemia.Toxicities include mild nausea, alopecia, allergic reaction, phlebitis at the injection site, and bone marrow toxicity.

• Manufacturing Process

  Preparation of 2,3-Di-O-dichloroacetyl-(4,6-O-ethylidene)-β-D-glucopyranose (hydrogenolysis)
  An over-dried 100 mL three-necked round bottom flask fitted with a stir bar, low temperature thermometer, and H2 inlet was charged with 2,3-di-Oetoposide dichloroacetyl-1-O-benzyloxycarbonyl-(4,6-O-ethylidene)-β-D-glucopyranose (1.8 mmol), in acetone (15-30% concentration) and 10% palladium on activated carbon powder (0.2 mmol). The solution was stirred until uniform and then cooled to -10°C to 0°C. After the reaction was over the catalyst was filtered over sintered glass containing a plug of celite under reduced pressure. The sintered glass is washed trice with one times the total reaction volume of anhydrous acetone and the filtrates are pooled and then concentrated to dryness under reduced pressure at a temperature close to 30°C. The crude residue was dried under vacuum at ambient temperature and above compound was thus obtained as white foam in 98% yield with a melting point of 130°-132°C (from acetone).
  Preparation of 4'-Demethyl-epi-podophyllotoxin-4-(2,3-di-O-dichloroacetyl- 4,6-O-ethylidene)-β-D-glucopyranoside
  An oven-dried, three-neck 250 mL round bottom flask was fitted with a stir bar, low temperature thermometer, septa and argon inlet, was introduced with 4'-demethyl-epi-podophyllotoxin (1 mmol), dry molecular sieve (1/16 δ pellets) and anhydrous dichloromethane (20-50% concentration). 2-3-Di-Odichloroacetyl-( 4,6-O-ethylidene)-β-D-glucopyranose (1.7 mmol) in dichloromethane (10-20% concentration) was added via double-ended needle. The suspension was stirred until homogenous and then cooled to -40°C to - 60°C in an atmosphere of argon and in the absence of moisture. To the stirred suspension was added via a syringe, trimethylsilyl trifluoromethane sulfonate (2 mmol) over 30 minutes. The reaction was held at between -50°C and - 40°C for 30 minutes. The course of the coupling reaction was monitored by thin layer chromatography. The suspension was allowed to warm to about - 30°C and filtered through a short celite/basic alumina column, eluting twice with one times the total reaction volume of dichloromethane. The pooled filtrate was evaporated under reduced pressure to yield the crude intermediate product 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-Odichloroacetyl- 4,6-O-ethylidene)-β-D-glucopyranose (yield 80%). This crude product is used directly in the next step without any purification. A sample was purified by the chromatraton for spectroscopic identification. The results are as follows: m.p.: 242°-243°C (from methanol).
  Preparation of 4-Demethyl-epi-podophyllotoxin-4-(4,6-O-ethylidene)-β-Dglucopyranose (etoposide)
  To 0.8 mmol of 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-O-dichloroacetyl- 4,6-O-ethylidene)-β-D-glucopyranose in 10-25% concentration in methanol is added 1.5 mmol of zinc acetate dihydrate. The reaction mixture is refluxed with stirring under heating for 90 minutes. After completion of the reaction, the mixture is cooled and the volume reduced to one third by rotary evaporation under reduced pressure. Working up is effected by diluting the reaction solution with 100 mL dichloromethane and 100 mL of water. The aqueous phase was washed with 50 mL of dichloromethane. The combined dichloromethane phases was washed twice with 50 mL water, 15 mL of methanol was added to the first wash to prevent precipitation of etoposide. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated by evaporation under vacuum to an amorphous solid. This solid was re-crystallized from methanol/n-pentane at -4°C to 0°C, thus obtaining colorless amorphous powder of Etoposide (yield 68%), if the mother liquors are treated the yield will be higher). Melting point: 256°-258°C.
  Preparation of Etoposide employing 2,3-di-O-dichloroacetyl-(4,6-Oethylidene)- β-D-glucopyranose and boron trifluoride etherate as catalyst
  4'-Demethyl-epi-podophyllotoxin (1 mmol) and 2,3-di-O-dichloroacetyl-(4,6

• Trademarks

  Toposar(Sicor); Vepesid (Bristol-Myers Squibb).

• Therapeutic Function

  Antitumor, Antineoplastic

• Allgemeine Beschreibung

  Etoposide is available in 50- and 100-mg capsules for oral useand in 100-mg vials for IV use. The agent is approved for usein testicular cancer and small cell lung cancer. It has alsobeen used in a wide variety of cancers including NSCLC,Hodgkin’s and non-Hodgkin’s disease, Kaposi sarcoma,acute lymphocytic leukemia, neuroblastoma, choriocarcinoma,and epithelial, ovarian, testicular, gastric, endometrial,and breast cancers. Etoposide is one of the few natural productderivatives that can be administered orally. When givenby this route, bioavailability is 50%. Administration by the IVroute is also utilized, and the drug is widely distributed whengiven by either route. The agent is highly protein bound(90%) primarily to albumin. Low albumin levels may lead toan increase in free drug and require a lowering of the dose.The drug does not penetrate the blood-brain barrier at normaldoses but does during high-dose therapy. Elimination occursprimarily in the urine with 30% to 40% of an IV dose appearingas unchanged drug. The elimination half-life is 5 to 10hours. Metabolism involves opening of the lactone ring togive the hydroxy acid as the major metabolite. Epimerizationoccurs at C-3 to give the cis-lactone, which may also undergohydrolysis to give the hydroxy acid. Glucuronidation and sulfationof the 4'-OH give products that are inactive. Activemetabolites are formed as a result of CYP3A4 mediated oxidative-O-demethylation of the 3'-methoxy group to give thecatechol followed by oxidation to give the quinone. The toxicitiesof etoposide include dose-limiting myelosuppression,produces nausea and vomiting in 30% to 40% of patients,which is more commonly seen when the drug is administeredorally. The agent also produces anorexia, alopecia, mucositis,and hypersensitivity reactions that may be caused by etoposideor Cremophor EL (polyoxyethylated castor oil), which isused as a vehicle for IV administration of the drug. Leukemia,especially acute myelogenous leukemia, has been associatedwith the drugs’ ability to produce strand breaks with resultanttranslocation of genetic material. The leukemias are generallyseen 5 to 8 years posttreatment and have been associated withtranslocation of several different genes resulting in breakpointsaround the mixed lineage leukemia (MLL) gene.Transcription and translation of this altered DNA giveschimeric proteins, which form partly from the translocatedgene and partly from the MLL gene. Exactly how thesechimeric proteins lead to leukemia is not known, but similaralterations are seen with other topoisomerase inhibitors.

• Biochem/physiol Actions

  Etoposide is an antitumor agent that complexes with topoisomerase II and DNA to enhance double-strand and single-strand cleavage of DNA and reversibly inhibit religation. Blocks the cell cycle in in S-phase and G2-phase of the cell cycle; induces apoptosis in normal and tumor cell lines; inhibits synthesis of the oncoprotein Mdm2 and induces apoptosis in tumor lines that overexpress Mdm2.

• Clinical Use

  Etoposide is utilized in the treatment of small cell lung cancer and in combination with other agents in refractory testicular cancer.

• Sicherheitsprofil

  Poison by ingestion, intraperitoneal, intravenous, and subcutaneous routes. An experimental teratogen. Human systemic effects by ingestion and inhalation: agranulocytosis, aplastic anemia, and other changes in bone marrow. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits acrid smoke and fumes.

• Synthese

  Etoposide, [[5R-(5|á,5a|?,8a|á,9|?)]-9-[4,6-O-ethylidene-|?-D-glucopyranosyl) oxy]-] 5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4: 6,7]-naphtho[2,3- d]-1,3-dioxol-6(5aH)-one (30.4.5), is made from 4-desmethylepipodophyllotoxin (30.4.3), the phenolic group of which being previously protected by benzyl chloroformate, which makes 4-carbobenzyloxy-4-desmethylepipodophyllotoxin (30.4.3). Next, the hydroxyl group at position C9 is esterified with 4,6-O-ethylyden-2,3-di-O-acetyl-|?-D-glucopyranose in the presence of boron trifluoride to make the corresponding glucopyranoside 30.4.4. Removing the acetyl group in the glucopyranosyl part of the molecule using zinc acetate in sodium methoxide, and also removing the benzyloxycarbonyl protection by hydrogenation using a palladium on carbon catalyst gives the desired etoposide (30.4.5).

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Anticoagulants: possibly enhanced anticoagulant effect with coumarins.
  Antipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosis.
  Ciclosporin: 50% reduction in etoposide clearance.

• Stoffwechsel

  The drug is more than 96% protein bound, undergoes biphasic elimination, and has a terminal half-life of 4 to 11 hours. Approximately 35 to 45% of a dose is eliminated via the kidneys, with less than 6% excreted in feces. The drug should be used with caution in patients with renal or liver disease.

• Lager

  Store at RT

• Einzelnachweise

  Hande, K. R. "Etoposide: four decades of development of a topoisomerase II inhibitor." European Journal of Cancer34.10(1998):1514.
  Noda, K, et al. "Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer." New England Journal of Medicine 346.2(2002):85-91.

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