Gemcitabine

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Gemcitabine
Gemcitabine.svg
Gemcitabine-hydrochloride-from-xtal-3D-balls.png
Systematic (IUPAC) name
4-amino-1-(2-deoxy-2,2-difluoro-β-D-erythro-pentofuranosyl)pyrimidin-2(1H)-on
Clinical data
Trade names Gemzar
AHFS/Drugs.com monograph
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
  • AU: S2 (Pharmacy only)
  • UK: POM (Prescription only)
  • US: ℞-only
Routes of
administration		 Oral, intravenous
Pharmacokinetic data
Protein binding <10%
Biological half-life Short infusions 32-94 minutes
for long infusions 245-638 minutes
Identifiers
CAS Number 95058-81-4 YesY
ATC code L01BC05 (WHO)
PubChem CID: 60750
IUPHAR/BPS 4793
DrugBank DB00441 YesY
ChemSpider 54753 YesY
UNII B76N6SBZ8R YesY
KEGG D02368 YesY
ChEBI CHEBI:175901 YesY
ChEMBL CHEMBL888 YesY
Chemical data
Formula C9H11F2N3O4
Molecular mass 263.198 g/mol
  • c1cn(c(=O)nc1N)[C@H]2C([C@@H]([C@H](O2)CO)O)(F)F
  • InChI=1S/C9H11F2N3O4/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17)/t4-,6-,7-/m1/s1 YesY
  • Key:SDUQYLNIPVEERB-QPPQHZFASA-N YesY
  (verify)

Gemcitabine (pronunciation: jem-SITE-a-been) is a nucleoside analog used as chemotherapy. It is marketed as Gemzar by Eli Lilly and Company.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[1]

Medical uses

Gemcitabine is used in various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. It is being investigated for use in esophageal cancer, and is used experimentally in lymphomas and various other tumor types. Gemcitabine represents an advance in pancreatic cancer care[citation needed]. It is also not as debilitating as some other forms of chemotherapy.

A study reported in the Journal of the American Medical Association in 2007 suggested that gemcitabine showed benefit in patients with pancreatic cancer who were felt to have successful tumor resections.[2]

Gemcitabine became first line treatment for bladder cancer Stage 4 with metastases in combination with cisplatin after a study in 2000 with 405 patients showed similar efficacy but less toxicity compared to the former MVAC regimen.[3] This new CG-regimen involves taking cisplatin on day 2 and taking gemcitabine on days 1, 8, and 15.

In July 2006 the FDA approved gemcitabine for use with carboplatin in the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based (e.g., carboplatin or cisplatin) therapy. Neutropenia was the most commonly reported adverse effect (90% of patients). Other serious adverse effects were mostly hematologic.

Gemcitabine was also investigated for advanced cancer of the biliary tract and gallbladder and was found to have a modest effect on the tumor when combined with cisplatin (NEJM 2010).

Lung cancer

GemCarbo chemotherapy, consisting of a combination of gemcitabine and carboplatin, is used to treat several different types of cancer, but is most commonly used to treat lung cancer.[4] GemCarbo chemotherapy is usually given as a day patient treatment, involving a blood test the day before, and the drugs are given by an infusion. The GemCarbo regimen is given as a 21-day cycle and on the first day of treatment the patient is given both the gemcitabine and carboplatin. On the same day of the following week (day eight) there is a drip of gemcitabine only. There then follows a rest period of two weeks which completes one cycle of chemotherapy. The next cycle of treatment is given after a rest period, which will be three weeks after the first injection. Usually 4–6 cycles of treatment are given over a period of 3–4 months and this makes up a course of treatment.

Administration

Gemcitabine is administered by the intravenous route, since it is extensively metabolized by the gastrointestinal tract.[5]

Side effects

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[citation needed]
  • Flu-like symptoms such as muscle pain, fever, headache, chills, and fatigue
  • Fever (within 6–12 hours of first dose)
  • Fatigue
  • Nausea (mild)
  • Vomiting
  • Poor appetite
  • Skin rash
  • Allergic reaction
  • Diarrhea
  • Weakness
  • Hair loss
  • Mouth sores
  • Difficulty sleeping
  • Shortness of breath

Pharmacology

Chemically gemcitabine is a nucleoside analog in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms.

As with fluorouracil and other analogues of pyrimidines, the triphosphate analogue of gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumor growth, as only one additional nucleoside can be attached to the "faulty" nucleoside, resulting in apoptosis.

Another target of gemcitabine is the enzyme ribonucleotide reductase (RNR). The diphosphate analogue binds to RNR active site and inactivates the enzyme irreversibly. Once RNR is inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair, and cell apoptosis is induced.[6]

History

Gemcitabine was first synthesized in Larry Hertel's lab at Eli Lilly during the early 1980s.[7] It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.[7] It was first licensed in the UK in 1995.

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Macmillan GemCarbo chemotherapy
  5. ↑ Chu E., DeVita V. T., "Physicians' Cancer Chemotherapy Drug Manual, 2007", Jones & Bartlett, 2007.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 Lua error in package.lua at line 80: module 'strict' not found.

External links

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