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.[5][6]
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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 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.[citation needed]
- White blood cells
- 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 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.[citation needed]
- Hematopoietic System
- G-CSF is also a potent inducer of hematopoietic stem cell (HSC) 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.[7]
- Neurons
- 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.[8][9] These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.[citation needed]
The gene for G-CSF is located on chromosome 17, locus q11.2-q12. Nagata et al. found that the GCSF gene has four introns, and that two different polypeptides are synthesized from the same gene by differential splicing of mRNA.[10]
The two polypeptides differ by the presence or absence of three amino acids. Expression studies indicate that both have authentic GCSF activity.[citation needed]
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.[citation needed]
Chemotherapy-induced neutropenia
Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cells (leukopenia), 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 and reduce mortality from neutropenia after chemotherapy, allowing higher-intensity treatment regimens.[11] It is administered to oncology patients via subcutaneous or intravenous routes.[12] A QSP model of neutrophil production and a PK/PD model of a cytotoxic chemotherapeutic drug (Zalypsis) have been developed to optimize the use of G-CSF in chemotherapy regimens with the aim to prevent mild-neutropenia.[13]
G-CSF was first trialled as a therapy for neutropenia induced by chemotherapy in 1988. The treatment was well tolerated and a dose-dependent rise in circulating neutrophils was noted.[14]
A study in mice has shown that G-CSF may decrease bone mineral density.[15]
G-CSF administration has been shown to attenuate the telomere loss associated with chemotherapy.[16]
The skin disease Sweet's syndrome is a known side effect of using this drug.[20]
Mouse granulocyte-colony stimulating factor (G-CSF) was first recognised and purified in Walter and Eliza Hall Institute, Australia in 1983,[21] and the human form was cloned by groups from Japan and Germany/United States in 1986.[10][22]
The FDA approved the first biosimilar of Neulasta in June 2018. It is made by Mylan and sold as Fulphila.[23]
The recombinant human G-CSF (rhG-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.[citation needed]
Filgrastim 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. Filgrastim (Neupogen) and PEG-filgrastim (Neulasta) are two commercially available forms of rhG-CSF. The PEG (polyethylene glycol) form has a much longer half-life, reducing the necessity of daily injections.
Another form of rhG-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.
Research
G-CSF when given early after exposure to radiation may improve white blood cell counts, and is stockpiled for use in radiation incidents.[24][25]
Mesoblast 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.[26]
G-CSF has been shown to reduce inflammation, reduce amyloid beta burden, and reverse cognitive impairment in a mouse model of Alzheimer's disease.[27]
Due to its neuroprotective properties, G-CSF is currently under investigation for cerebral ischemia in a clinical phase IIb [28] and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis[29] A combination of human G-CSF and cord blood cells has been shown to reduce impairment from chronic traumatic brain injury in rats.[30]
Deotare U, Al-Dawsari G, Couban S, Lipton JH (September 2015). "G-CSF-primed bone marrow as a source of stem cells for allografting: revisiting the concept". Bone Marrow Transplantation. 50 (9): 1150–1156. doi:10.1038/bmt.2015.80. PMID 25915812. S2CID 20774089. Craig M, Humphries AR, Nekka F, Bélair J, Li J, Mackey MC (November 2015). "Neutrophil dynamics during concurrent chemotherapy and G-CSF administration: Mathematical modelling guides dose optimisation to minimise neutropenia". Journal of Theoretical Biology. 385: 77–89. Bibcode:2015JThBi.385...77C. doi:10.1016/j.jtbi.2015.08.015. PMID 26343861. Szyper-Kravitz M, Uziel O, Shapiro H, Radnay J, Katz T, Rowe JM, et al. (January 2003). "Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy". British Journal of Haematology. 120 (2): 329–336. doi:10.1046/j.1365-2141.2003.04043.x. PMID 12542495. S2CID 5785335. Finkel E (2005). Stem cells: controversy on the frontiers of science. Crows Nest: ABC Books. ISBN 978-0-7333-1248-9. Zhang Y, Wang L, Fu Y, Song H, Zhao H, Deng M, et al. (2009). "Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis". Amyotrophic Lateral Sclerosis. 10 (5–6): 430–431. doi:10.3109/17482960802588059. PMID 19922135. S2CID 43087598.
- Duarte RF, Frank DA (June 2002). "The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): molecular basis and clinical relevance". Leukemia & Lymphoma. 43 (6): 1179–1187. doi:10.1080/10428190290026231. PMID 12152985. S2CID 45748453.
- Mroczko B, Szmitkowski M (2005). "Hematopoietic cytokines as tumor markers". Clinical Chemistry and Laboratory Medicine. 42 (12): 1347–1354. doi:10.1515/CCLM.2004.253. PMID 15576295. S2CID 11414705.
- Sallerfors B, Olofsson T (October 1992). "Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) secretion by adherent monocytes measured by quantitative immunoassays". European Journal of Haematology. 49 (4): 199–207. doi:10.1111/j.1600-0609.1992.tb00047.x. PMID 1281454. S2CID 35573524.
- Zink T, Ross A, Ambrosius D, Rudolph R, Holak TA (December 1992). "Secondary structure of human granulocyte colony-stimulating factor derived from NMR spectroscopy". FEBS Letters. 314 (3): 435–439. Bibcode:1992FEBSL.314..435Z. doi:10.1016/0014-5793(92)81521-M. PMID 1281794. S2CID 28422738.
- Kubota N, Orita T, Hattori K, Oh-eda M, Ochi N, Yamazaki T (March 1990). "Structural characterization of natural and recombinant human granulocyte colony-stimulating factors". Journal of Biochemistry. 107 (3): 486–492. doi:10.1093/oxfordjournals.jbchem.a123072. PMID 1692828.
- Nagata S, Tsuchiya M, Asano S, Yamamoto O, Hirata Y, Kubota N, et al. (March 1986). "The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor". The EMBO Journal. 5 (3): 575–581. doi:10.1002/j.1460-2075.1986.tb04249.x. PMC 1166801. PMID 2423327.
- Tweardy DJ, Cannizzaro LA, Palumbo AP, Shane S, Huebner K, Vantuinen P, et al. (August 1987). "Molecular cloning and characterization of a cDNA for human granulocyte colony-stimulating factor (G-CSF) from a glioblastoma multiforme cell line and localization of the G-CSF gene to chromosome band 17q21". Oncogene Research. 1 (3): 209–220. PMID 2453015.
- Tsuchiya M, Nomura H, Asano S, Kaziro Y, Nagata S (March 1987). "Characterization of recombinant human granulocyte-colony-stimulating factor produced in mouse cells". The EMBO Journal. 6 (3): 611–616. doi:10.1002/j.1460-2075.1987.tb04798.x. PMC 553441. PMID 3034599.
- Devlin JJ, Devlin PE, Myambo K, Lilly MB, Rado TA, Warren MK (April 1987). "Expression of granulocyte colony-stimulating factor by human cell lines". Journal of Leukocyte Biology. 41 (4): 302–306. doi:10.1002/jlb.41.4.302. PMID 3494801. S2CID 26877622.
- Kanda N, Fukushige S, Murotsu T, Yoshida MC, Tsuchiya M, Asano S, et al. (November 1987). "Human gene coding for granulocyte-colony stimulating factor is assigned to the q21-q22 region of chromosome 17". Somatic Cell and Molecular Genetics. 13 (6): 679–684. doi:10.1007/BF01534488. PMID 3499671. S2CID 10909775.
- Le Beau MM, Lemons RS, Carrino JJ, Pettenati MJ, Souza LM, Diaz MO, et al. (December 1987). "Chromosomal localization of the human G-CSF gene to 17q11 proximal to the breakpoint of the t(15;17) in acute promyelocytic leukemia". Leukemia. 1 (12): 795–799. PMID 3501046.
- Zink T, Ross A, Lüers K, Cieslar C, Rudolph R, Holak TA (July 1994). "Structure and dynamics of the human granulocyte colony-stimulating factor determined by NMR spectroscopy. Loop mobility in a four-helix-bundle protein". Biochemistry. 33 (28): 8453–8463. doi:10.1021/bi00194a009. PMID 7518249.
- Corcione A, Baldi L, Zupo S, Dono M, Rinaldi GB, Roncella S, et al. (October 1994). "Spontaneous production of granulocyte colony-stimulating factor in vitro by human B-lineage lymphocytes is a distinctive marker of germinal center cells". Journal of Immunology. 153 (7): 2868–2877. doi:10.4049/jimmunol.153.7.2868. PMID 7522243. S2CID 25302361.
- Watari K, Ozawa K, Tajika K, Tojo A, Tani K, Kamachi S, et al. (July 1994). "Production of human granulocyte colony stimulating factor by various kinds of stromal cells in vitro detected by enzyme immunoassay and in situ hybridization". Stem Cells. 12 (4): 416–423. doi:10.1002/stem.5530120409. PMID 7524894. S2CID 22671177.
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- Haniu M, Horan T, Arakawa T, Le J, Katta V, Rohde MF (December 1995). "Extracellular domain of granulocyte-colony stimulating factor receptor. Interaction with its ligand and identification of a domain in close proximity of ligand-binding region". Archives of Biochemistry and Biophysics. 324 (2): 344–356. doi:10.1006/abbi.1995.0047. PMID 8554326.
- McCracken S, Layton JE, Shorter SC, Starkey PM, Barlow DH, Mardon HJ (May 1996). "Expression of granulocyte-colony stimulating factor and its receptor is regulated during the development of the human placenta". The Journal of Endocrinology. 149 (2): 249–258. doi:10.1677/joe.0.1490249. PMID 8708536.
