Gemcitabine

Gemcitabine
Clinical data
Pronunciation jem-SEYE-tə-been
Trade names Gemzar
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration		 Intravenous
ATC code L01BC05 (WHO)
Legal status
Legal status
  • AU: S2 (Pharmacy only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Pharmacokinetic data
Protein binding <10%
Biological half-life Short infusions: 32–94 minutes
Long infusions: 245–638 minutes
Identifiers
CAS Number 95058-81-4 YesY
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
ECHA InfoCard 100.124.343
Chemical and physical data
Formula C9H11F2N3O4
Molar mass 263.198 g/mol
3D model (Jmol) Interactive image
  (verify)

Gemcitabine is a nucleoside analog used in 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 is administered by the intravenous route, since it is extensively metabolized by the gastrointestinal tract.[2]

Bladder cancer

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.

Ovarian cancer

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.

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.

Side effects

  • 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.[5]

History

Gemcitabine was first synthesized in Larry Hertel's lab at Eli Lilly during the early 1980s.[6] It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.[6] It was first licensed in the UK in 1995.

Research

Pancreatic cancer

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.[7]

The addition of capecitabine to gemcitabine was studied in the ESPAC-4 trial and found beneficial.[8][9]

Other

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).

As with many nucleoside analogues, gemcitabine may show antiviral activity as well as anti-cancer properties. Preliminary in vitro and mouse studies have shown it to be effective against enteroviruses such as coxsackievirus and poliovirus, as well as showing weaker activity against rhinoviruses, influenza and HIV, though it remains unclear whether gemcitabine is safe and effective enough in these applications to be developed for medical use as an antiviral agent.[10][11][12][13]

See also

References

  1. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  2. ↑ Chu E., DeVita V. T., "Physicians' Cancer Chemotherapy Drug Manual, 2007", Jones & Bartlett, 2007.
  3. ↑ Von Der Maase, H; Hansen, SW; Roberts, JT; Dogliotti, L; Oliver, T; Moore, MJ; Bodrogi, I; Albers, P; et al. (2000). "Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study". J Clin Oncol. 18 (17): 3068–77. PMID 11001674.
  4. ↑ Macmillan GemCarbo chemotherapy
  5. ↑ Cerqueira NM, Fernandes PA, Ramos MJ (2007). "Understanding ribonucleotide reductase inactivation by gemcitabine". Chemistry: A European Journal. 13 (30): 8507–15. doi:10.1002/chem.200700260. PMID 17636467.
  6. 1 2 Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 259. ISBN 0-471-89979-8.
  7. ↑ Oettle H, Post S, Neuhaus P, et al. (January 2007). "Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial". JAMA. 297 (3): 267–77. doi:10.1001/jama.297.3.267. PMID 17227978.
  8. ↑ Trial Sets New Standard for Pancreatic Cancer - Adjuvant combination almost doubled 5-year survival. June 2016
  9. ↑ ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. June 2016
  10. ↑ Clouser CL, Holtz CM, Mullett M, Crankshaw DL, Briggs JE, O'Sullivan MG, Patterson SE, Mansky LM. Activity of a novel combined antiretroviral therapy of gemcitabine and decitabine in a mouse model for HIV-1. Antimicrob Agents Chemother. 2012 Apr;56(4):1942-8. doi: 10.1128/AAC.06161-11. PMID 22271861
  11. ↑ Denisova OV, Kakkola L, Feng L, Stenman J, Nagaraj A, Lampe J, Yadav B, Aittokallio T, Kaukinen P, Ahola T, Kuivanen S, Vapalahti O, Kantele A, Tynell J, Julkunen I, Kallio-Kokko H, Paavilainen H, Hukkanen V, Elliott RM, De Brabander JK, Saelens X, Kainov DE. Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection. J Biol Chem. 2012 Oct 12;287(42):35324-32. doi: 10.1074/jbc.M112.392142. PMID 22910914
  12. ↑ Kang H, Kim C, Kim DE, Song JH, Choi M, Choi K, Kang M, Lee K, Kim HS, Shin JS, Kim J, Han SB, Lee MY, Lee SU, Lee CK, Kim M, Ko HJ, van Kuppeveld FJ, Cho S. Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses. Antiviral Res. 2015 Dec;124:1-10. doi: 10.1016/j.antiviral.2015.10.011. PMID 26526589
  13. ↑ Zhang Z, Yang E, Hu C, Cheng H, Chen CY, Huang D, Wang R, Zhao Y, Rong L, Vignuzzi M, Shen H, Shen L, Chen ZW. Cell-based high-throughput screening assay identifies 2', 2'-difluoro-2'-deoxycytidine Gemcitabine as potential anti-poliovirus agent. ACS Infect Dis. 2016 Oct 12. PMID 27733043
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