Gemcitabine

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H312：Gesundheitsschädlich bei Hautkontakt.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H340：Kann genetische Defekte verursachen.

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

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

Gemcitabine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R21:Gesundheitsschädlich bei Berührung mit der Haut.
  R36/38:Reizt die Augen und die Haut.
  R46:Kann vererbbare Schäden verursachen.
  R62:Kann möglicherweise die Fortpflanzungsfähigkeit beeinträchtigen.
  R63:Kann das Kind im Mutterleib möglicherweise schädigen.

• S-Sätze Betriebsanweisung:

  S25:Berührung mit den Augen vermeiden.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.

• Beschreibung

  Gemcitabine is an anticancer nucleoside analog that inhibits the growth of HL-60 promyelocytic leukemia cells with an LC₅₀ value of 40 nM. It inhibits the growth of MX-1 mammary, CX-1, HC-1, GC3, and VRC5 colon, LX-1, Calu-6, and NCI-H460 lung, and HS766T, PaCa-2, PANC-1, and BxPC-3 pancreatic cancer tumors in mouse xenograft models (45-93% inhibition). Gemcitabine is a prodrug that is metabolized to a diphosphate and triphosphate form in cells. The triphosphate form is incorporated into DNA which induces masked chain termination and cell death. By specifically inhibiting growth arrest and DNA damage inducible protein 45 a (Gadd45a), a key mediator of active DNA demethylation, gemcitabine, at concentrations ranging from 34 to 134 nM, inhibits repair-mediated DNA demethylation in a methylation-sensitive reporter assay. Gemcitabine also has broad antiretroviral activity, decreasing MuLV cell infectivity, a murine AIDS model, in cell culture (EC₅₀ = ~1.5 nM) and inhibits the progression of murine AIDS in vivo at a dose of 1-2 mg/kg per day.

• Originator

  Gemzar,Lilly Co.

• Verwenden

  Gemcitabine is used for breast cancer treatment. First-line treatment for locally advanced pancreatic cancer.

• Verwenden

  Gemcitabine(Gemzar) belongs to the group of medicines called antimetabolites. It is used alone or in combination with other medicines to treat cancer of the breast, ovary, pancreas, and lung. Gemcitabine interferes with the growth of cancer cells, which a

• Definition

  ChEBI: Gemcitabine is a 2'-deoxycytidine having geminal fluoro substituents in the 2'-position. An inhibitor of ribonucleotide reductase, gemcitabine is used in the treatment of various carcinomas, particularly non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. It has a role as a photosensitizing agent, a DNA synthesis inhibitor, a prodrug, an EC 1.17.4.1 (ribonucleoside-diphosphate reductase) inhibitor, an environmental contaminant, a xenobiotic, a radiosensitizing agent, an antineoplastic agent, an antimetabolite, an antiviral drug and an immunosuppressive agent. It is an organofluorine compound and a pyrimidine 2'-deoxyribonucleoside.

• Indications

  Gemcitabine (Gemzar), an antimetabolite, undergoes metabolic activation to difluorodeoxycytidine triphosphate, which interferes with DNA synthesis and repair. It is the single most active agent for the treatment of metastatic pancreatic cancer, and it is used as a first-line treatment for both pancreatic and small cell lung cancer. It is administered by intravenous infusion. The dose-limiting toxicity is bone marrow suppression.

• Manufacturing Process

  Benzyl 4,6-O-benzylidene-2-O-benzyl-3-oxo-α-D-gluco-pyranoside was obtained by 4 steps from glucose.
  0.53 ml (4.0 mmol) of DAST (fluorinaiting agent) was added to asolution of 300 mg (0.67 mmol) of benzyl 4,6-O-benzylidene-2-O-benzyl-3-oxo-α-Dgluco-pyranoside in anhydrous dichloromethane (4 ml). The solution was then stirred at room temperature for 2 h, and the excess of DAST was neutralized by careful addition of saturated aqueous NaHCO3. The resulting mixture was extracted with CH2Cl2, and organic phase was dried and evaporated. The residue was purified by CC (Hexane/Ethyl acetate 7:1) to afford benzyl 4,6-Obenzylidene-2-O-benzyl-3-deoxy-3,3-difluoro-α-D-gluco-pyranoside (189 mg, 60%), melting point 118°-119°C.
  Benzyl 4,6-O-benzylidene-2-O-benzyl-3-deoxy-3,3-difluoro-α-D-glucopyranoside (77 mg, 0.16 mmol) was dissolved in a 0.1 N solution of HCl in ethanol and stirred at room temperature for 40 h. The solution was then neutralized with solid NaHCO3, filtered and evaporated to give an oily product that was dissolved in 2 ml of CH2Cl2 and 0.5 ml of pyridine. After cooling to 0°C, 0.40 ml (1.6 mmol) of benzoyl chloride was added and the solution was stirred for 1 h and poured into ice and water (200 ml) containing NaHCO3, extracted several times with CH2Cl2, dried and evaporated to give 86 mg (0.14 mmol, 90%) of benzyl 4,6-di-O-benzoyl-2-O-benzyl-3-deoxy-3,3- difluoro-α-D-gluco-pyranoside.
  Benzyl 4,6-di-O-benzoyl-2-O-benzyl-3-deoxy-3,3-difluoro-α-D-glucopyranoside (220 mg, 0.44 mmol) was dissolved in methanol in the presence of 200 mg of palladium on activated charcoal (10% Pd content). The suspension was stirred at room temperature under hydrogen pressure (10 bar) for 16 h. The suspension was then filtered through a thin silica gel pad, and evaporated. The residue was purified by CC to give 105 mg (59%) of 4,6- di-O-benzoyl-3-deoxy-3,3-difluoro-α/β-D-gluco-pyranoside as an inseparable anomeric mixture (ratio α/β = 5:1).
  To a solution of 46 mg (0.11 mmol) of 4,6-di-O-benzoyl-3-deoxy-3,3-difluoro- α/β-D-gluco-pyranoside in water-dioxane 1:2 (2 ml) was added 120 mg (0.56 mmol) of sodium periodate. This resulting solution was stirred at room temperature for 20 h. Then, more sodium periodate (55 mg, 0.26 mmol) was added and stirring was continued for 6 h. After that, the solvents were evaporated and the solid was repeatedly extracted with ethyl acetate (total volume 70 ml). The solvent was then evaporated to give a solid that was treated for 15 min with a diluted (0.1%) methanolic solution of ammonia. THE solution was evaporated and the crude purified by preparative TLC (hexane/ethyl acetate 2:1) to yield 18 mg (0.04 mmol, 43%) of α-3,5-di-Obenzoyl-2-deoxy-2,2-difluoro-D-ribose.

• Therapeutic Function

  Antineoplastic, Antiviral

• Allgemeine Beschreibung

  The drug is available as the hydrochloride salt in 200- and1,000-mg lyophilized single-dose vials for IV use.Gemcitabine is used to treat bladder cancer, breast cancer,pancreatic cancer, and NSCLC. Gemcitabine is a potent radiosensitizer,and it increases the cytotoxicity of cisplatin.The mechanism of action of this fluorine-substituted deoxycytidineanalog involves inhibition of DNA synthesis andfunction via DNA chain termination. The triphosphatemetabolite is incorporated into DNA inhibiting severalDNA polymerases and incorporated into RNA inhibitingproper function of mRNA. Resistance can occur because ofdecreased expression of the activation enzyme deoxycytidinekinase or decreased drug transport as well as increasedexpression of catabolic enzymes. Drug oral bioavailabilityis low because of deamination within the GI tract, and thedrug does not cross the blood-brain barrier. Metabolism bydeamination to 2', 2'-difluorouridine (dFdU) is extensive.Drug toxicity includes myelosuppression, fever, malaise,chills, headache, myalgias, nausea, and vomiting.

• Hazard

  Human systemic effects

• Mechanism of action

  Gemcitabine shows good activity against human leukemic cell lines, a number of murine solid tumors, and human tumor xenografts. Gemcitabine was significantly more cytotoxic than cytarabine in Chinese hamster ovary cells. The major cellular metabolite is the 5'-triphosphate of gemcitabine. The cytotoxicity was competitively reversed by deoxycytidine, suggesting that the biological activity required phosphorylation by deoxycytidine kinase. Tumor-bearing mice were treated with either gemcitabine or cytarabine (20 mg/kg). DNA synthesis reached 1 % of control levels upon administration of gemcitabine. The greater accumulation of gemcitabine-5'-triphosphate compared with cytarabine-5'-triphosphate may cause greater cytotoxicity and therapeutic activity. Further gemcitabine may enhance its own cytotoxic effects by self-potentiation mechanisms that act on, e. g., deoxycytidine monophosphate deaminase, deoxycytidine kinase or on DNA synthesis.

• Clinical Use

  Antineoplastic agent:
  
  Palliative treatment, or first-line treatment with cisplatin, of locally advanced or metastatic non-small cell lung cancer
  
  Pancreatic, ovarian and breast cancer
  
  Bladder cancer in combination with cisplatin

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

• Stoffwechsel

  After intravenous doses gemcitabine is rapidly cleared from the blood and metabolised by cytidine deaminase in the liver, kidney, blood, and other tissues. Clearance is about 25% lower in women than in men.
  Almost all (99%) of the dose is excreted in urine as 2′-deoxy-2′,2′-difluorouridine (dFdU), only about 1% being found in the faeces. Intracellular metabolism produces mono-, di-, and triphosphate metabolites, the latter two active. The active intracellular metabolites have not been detected in plasma or urine.

• Einzelnachweise

  [1] karnitz lm, flatten ks, wagner jm, et al. gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. mol pharmacol, 2005, 68 (6): 1636-1644.
  [2] ando t, ichikawa j, okamoto a, et al. gemcitabine inhibits viability, growth, and metastasis of osteosarcoma cell lines. j orthop res, 2005, 23 (4): 964-969.
  [3] clouser cl, holtz cm, mullett m, et al. analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. plos one, 2011, 6 (1): e15840.

Gemcitabine Upstream-Materialien And Downstream Produkte

Gemcitabine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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