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 and 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 .
Biological function
- 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 . G-CSF stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature . 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.
- 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.
- 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. These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.
Genetics
The two polypeptides differ by the presence or absence of three 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.
Medical use
Chemotherapy-induced neutropenia
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.
A study in mice has shown that G-CSF may decrease bone mineral density.
G-CSF administration has been shown to attenuate the telomere loss associated with chemotherapy.
Use in drug-induced neutropenia
Before blood donation
Stem cell transplants
Side effect
History
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.
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.
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). 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 United States.
Pharmaceutical variants
The Food and Drugs Administration (FDA) first approved filgrastim on February 20, 1991 marketed by Amgen with the brand name Neupogen. 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.
Several bio-generic versions are now also available in markets such as Europe and Australia. Filgrastim (Neupogen) and Pegfilgrastim (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.
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.
Research
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.
G-CSF has been shown to reduce inflammation, reduce amyloid beta burden, and reverse cognitive impairment in a mouse model of Alzheimer's disease.
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 A combination of human G-CSF and cord blood cells has been shown to reduce impairment from chronic traumatic brain injury in rats.
See also
Further reading
External links
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