Granulocyte colony-stimulating factor

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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.<ref name="pmid25915812">Template:Cite journal</ref><ref name="pmid27943116">Template:Cite journal</ref>

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.

Biological functionEdit

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.<ref name=":0">Template:Cite journal</ref>

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.Template: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.<ref name="pmid11953662">Template:Cite journal</ref>

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.<ref name="pmid16007267">Template:Cite journal</ref><ref name="pmid18835867">Template:Cite journal</ref> These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.<ref>Template:Cite journal</ref>

GeneticsEdit

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.<ref name="pmid3484805">Template:Cite journal</ref>

The two polypeptides differ by the presence or absence of three amino acids. Expression studies indicate that both have authentic GCSF activity.Template: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.Template:Citation needed

Medical useEdit

Chemotherapy-induced neutropeniaEdit

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.<ref name="pmid23788754">Template:Cite journal</ref> It is administered to oncology patients via subcutaneous or intravenous routes.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

A study in mice has shown that G-CSF may decrease bone mineral density.<ref name="pmid17192391">Template:Cite journal</ref>

G-CSF administration has been shown to attenuate the telomere loss associated with chemotherapy.<ref name="pmid12542495">Template:Cite journal</ref>

Use in drug-induced neutropeniaEdit

Neutropenia can be a severe side effect of clozapine, an antipsychotic medication in the treatment of schizophrenia. G-CSF can restore neutrophil count. Following a return to baseline after stopping the drug, it may sometimes be safely rechallenged with the added use of G-CSF.<ref name="Myles">Template:Cite journal</ref><ref name="Lally">Template:Cite journal</ref>

Before blood donationEdit

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.<ref name=Pessach2013>Template:Cite journal</ref> Breastfeeding should be withheld for three days after CSF administration to allow for clearance of it from the milk.<ref name=Pessach2013/> People who have been administered colony-stimulating factors do not have a higher risk of leukemia than people who have not.<ref name=Pessach2013/>

Stem cell transplantsEdit

G-CSF may also be given to the receiver in hematopoietic stem cell transplantation, to compensate for conditioning regimens.<ref name="pmid12542495" />

Side effectEdit

The skin disease Sweet's syndrome is a known side effect of using this drug.<ref name="pmid7504506">Template:Cite journal</ref>

HistoryEdit

Two research teams independently identified mouse colony stimulating factors in the 1960s: Ray Bradley at University of Melbourne and Donald Metcalf at Walter and Eliza Hall Institute, from Australia, and Yasuo Ichikawa, Dov Pluznik and Leo Sachs at the Weizmann Institute of Science, Israel.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":0" /> In 1980 Antony Burgess and Donald Metcalf discovered that mouse lung conditioned medium contained at least two different CSFs <ref> Template:Cite journal </ref> - GM-CSF, which they had purified in 1977 and a G-CSF which stimulated the production of colonies of neutrophils.

In 1983, Donald Metcalf's research team, led by Nicos Nicola, isolated the murine cytokine from medium conditioned with lung tissue obtained from endotoxin-treated mice.<ref>Template:Cite journal</ref><ref name="pmid2990035">Template:Cite journal</ref><ref name=":0" />

In 1985, Karl Welte, Erich Platzer, Janice Gabrilove, Roland Mertelsmann and Malcolm Moore at the Memorial Sloan Kettering Cancer Center (MSK) purified human G-CSF produced by bladder cancer cell line 5637 from conditioned medium.<ref>Template:Cite journal</ref><ref name=":0" />

In 1986, Karl Welte's team at MSK patented the method of producing and using human G-CSF under the name "human hematopoietic pluripotent colony stimulating factor" or "human pluripotent colony stimulating factor" (P-CSF).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Also in 1986, two independent research groups working with pharmaceutical companies cloned the G-CSF gene that made possible large-scale production and its clinical use: Shigekazu Nagata's team in collaboration with Chugai Pharmaceutical Co. from Japan, and Lawrence Souza's team at Amgen in collaboration with Karl Welte's research team members from Germany and the USA.<ref name="pmid3484805" /><ref name="pmid2420009">Template:Cite journal</ref><ref name=":0" />

Pharmaceutical variantsEdit

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.Template:Citation needed

The Food and Drugs Administration (FDA) first approved filgrastim on February 20, 1991 marketed by Amgen with the brand name Neupogen.<ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was initially approved to reduce the risk of infection in patients with non-myeloid malignancies who are taking myelosuppressive anti-cancer drugs associated with febrile neutropenia with fever.<ref name=":1" />

Several bio-generic versions are now also available in markets such as Europe and Australia. Filgrastim (Neupogen) and PEG-filgrastim (Neulasta), or pegylated form of filgratim, are two commercially available forms of rhG-CSF. The pegylated form of filgratim form has a much longer half-life, reducing the necessity of daily injections.

The FDA approved the first biosimilar of Neulasta in June 2018. It is made by Mylan and sold as Fulphila.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.

In 2015, filgrastim was included on the WHO Model List of Essential Medicines, a list containing the medications considered to be most effective and safe to meet the most important needs in a health system.<ref name=":2">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ResearchEdit

G-CSF when given early after exposure to radiation may improve white blood cell counts, and is stockpiled for use in radiation incidents.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="isbn0-7333-1248-9">Template:Cite book</ref>

G-CSF has been shown to reduce inflammation, reduce amyloid beta burden, and reverse cognitive impairment in a mouse model of Alzheimer's disease.<ref name="pmid19500657">Template:Cite journal</ref>

Due to its neuroprotective properties, G-CSF is currently under investigation for cerebral ischemia in a clinical phase IIb <ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis<ref name="pmid19922135">Template:Cite journal</ref> A combination of human G-CSF and cord blood cells has been shown to reduce impairment from chronic traumatic brain injury in rats.<ref name="pmid24621603">Template:Cite journal</ref>

ReferencesEdit

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External linksEdit

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