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Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Functionally, it is a cytokine and hormone, a type of colony-stimulating factor, and is produced by a number of different tissues. The pharmaceutical analogs of naturally occurring G-CSF are called filgrastim and lenograstim.

G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway.

Discovery

Mouse granulocyte-colony stimulating factor (G-CSF) was first recognised and purified in Walter and Eliza Hall Institute, Australia in 1983, and the human form was cloned by groups from Japan and Germany/United States in 1986.

Biological function

G-CSF is produced by endothelium, macrophages, and a number of other immune cells. The natural human glycoprotein exists in two forms, a 174- and 177-amino-acid-long protein of molecular weight 19,600 grams per mole. The more-abundant and more-active 174-amino acid form has been used in the development of pharmaceutical products by recombinant DNA (rDNA) technology.

The G-CSF-receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates proliferation and differentiation into mature granulocytes. G-CSF is also a potent inducer of HSCs mobilization from the bone marrow into the bloodstream, although it has been shown that it does not directly affect the hematopoietic progenitors that are mobilized.

Beside the effect on the hematopoietic system, G-CSF can also act on neuronal cells as a neurotrophic factor. Indeed, its receptor is expressed by neurons in the brain and spinal cord. The action of G-CSF in the central nervous system is to induce neurogenesis, to increase the neuroplasticity and to counteract apoptosis. These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.

Genetics

The gene for G-CSF is located on chromosome 17, locus q11.2-q12. Nagata et al. found that the GCSF gene has 4 introns, and that 2 different polypeptides are synthesized from the same gene by differential splicing of mRNA.

The 2 polypeptides differ by the presence or absence of 3 amino acids. Expression studies indicate that both have authentic GCSF activity.

It is thought that stability of the G-CSF mRNA is regulated by an RNA element called the G-CSF factor stem-loop destabilising element.

Therapeutic use

Chemotherapy induced neutropenia

Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cells (neutropenia), making patients susceptible to infections and sepsis. G-CSF stimulates the production of granulocytes, a type of white blood cell. In oncology and hematology, a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery from neutropenia after chemotherapy, allowing higher-intensity treatment regimens. It is administered to oncology patients via subcutaneous or intravenous routes.

A Washington University School of Medicine study in mice has shown that G-CSF may decrease bone mineral density.

Before blood donation

G-CSF is also used to increase the number of hematopoietic stem cells in the blood of the donor before collection by leukapheresis for use in hematopoietic stem cell transplantation. For this purpose, G-CSF appears to be safe in pregnancy during implantation as well as during the second and third trimesters. Breastfeeding should be withheld for 3 days after CSF administration to allow for clearance of it from the milk.

Stem cell transplants

G-CSF may also be given to the receiver in hematopoietic stem cell transplantation, to compensate for conditioning regimens.

Research

Itescu planned in 2004 to use G-CSF to treat heart degeneration by injecting it into the blood-stream, plus SDF (stromal cell-derived factor) directly to the heart.

Due to its neuroprotective properties, G-CSF is currently under investigation for cerebral ischemia in a clinical phase IIb and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis.

Side effect

Sweet's syndrome is a known side effect of using this drug.

Pharmaceutical variants

It was first marketed by Amgen with the brand name Neupogen. Several bio-generic versions are now also available in markets such as Europe and Australia.

The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim. The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim. Filgrastim (Neupogen) and PEG-filgrastim (Neulasta) are two commercially-available forms of rhG-CSF (recombinant human G-CSF). The PEG (polyethylene glycol) form has a much longer half-life, reducing the necessity of daily injections.

Another form of recombinant human G-CSF called lenograstim is synthesised in Chinese Hamster Ovary cells (CHO cells). As this is a mammalian cell expression system, lenograstim is indistinguishable from the 174-amino acid natural human G-CSF. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies.

G-CSF when given early after exposure to radiation may improve white blood cell counts, and is stockpiled for use in radiation incidents.

People who have been administered colony-stimulating factors do not have a higher risk of leukemia than people who have not.

See also

• PEGylation

References

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2. ^ Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H (1986). "Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor". Nature. 319 (6052): 415–8. doi:10.1038/319415a0. PMID 3484805.{{cite journal}}: CS1 maint: multiple names: authors list (link)
3. Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, Barendt J, Platzer, E, Moore, MAS, Mertelsmann R, Welte K (April 1986). "Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells". Science. 232 (4746): 61–5. doi:10.1126/science.2420009. PMID 2420009.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. Thomas J, Liu F, Link DC (May 2002). "Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor". Curr. Opin. Hematol. 9 (3): 183–9. doi:10.1097/00062752-200205000-00002. PMID 11953662.{{cite journal}}: CS1 maint: multiple names: authors list (link)
5. Schneider A, Krüger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schäbitz WR (August 2005). "The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis". J. Clin. Invest. 115 (8): 2083–98. doi:10.1172/JCI23559. PMC 1172228. PMID 16007267.{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. Pitzer C, Krüger C, Plaas C, Kirsch F, Dittgen T, Müller R, Laage R, Kastner S, Suess S, Spoelgen R, Henriques A, Ehrenreich H, Schäbitz WR, Bach A, Schneider A (December 2008). "Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis". Brain. 131 (Pt 12): 3335–47. doi:10.1093/brain/awn243. PMC 2639207. PMID 18835867.{{cite journal}}: CS1 maint: multiple names: authors list (link)
7. "Granulocyte colony stimulating factor (G-CSF)". Cancer Research UK. Retrieved 12 November 2014.
8. Hirbe AC, Uluçkan O, Morgan EA, Eagleton MC, Prior JL, Piwnica-Worms D, Trinkaus K, Apicelli A, Weilbaecher K (April 2007). "Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner". Blood. 109 (8): 3424–31. doi:10.1182/blood-2006-09-048686. PMC 1852257. PMID 17192391.{{cite journal}}: CS1 maint: multiple names: authors list (link)
9. ^ Pessach I, Shimoni A, Nagler A (2013). "Granulocyte-colony stimulating factor for hematopoietic stem cell donation from healthy female donors during pregnancy and lactation: what do we know?". Hum. Reprod. Update. 19 (3): 259–67. doi:10.1093/humupd/dms053. PMID 23287427.{{cite journal}}: CS1 maint: multiple names: authors list (link)
10. Finkel, Elizabeth (2005). Stem cells: controversy on the frontiers of science. Crows Nest: ABC Books. ISBN 0-7333-1248-9.
11. http://clinicaltrials.gov/ct/show/NCT00927836
12. Zang Y et al. Amyotroph Lateral Scler. 2008 Dec 4:1-2 Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis.
13. Paydaş S, Sahin B, Seyrek E, Soylu M, Gonlusen G, Acar A, Tuncer I (September 1993). "Sweet's syndrome associated with G-CSF". Br. J. Haematol. 85 (1): 191–2. doi:10.1111/j.1365-2141.1993.tb08668.x. PMID 7504506.{{cite journal}}: CS1 maint: multiple names: authors list (link)
14. Weisdorf D, Chao N, Waselenko JK, et al. (June 2006). "Acute radiation injury: contingency planning for triage, supportive care, and transplantation". Biol. Blood Marrow Transplant. 12 (6): 672–82. doi:10.1016/j.bbmt.2006.02.006. PMID 16737941.
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Further reading

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External links

• Granulocyte+Colony-Stimulating+Factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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• Articles with unsourced statements from Nov 2015
• Growth factors
• Peptide hormones
• Amgen
• Cytokines
• Drugs acting on the blood and blood forming organs