G-CSF also stimulates the survival, proliferation, differentiation, and function of
neutrophil precursors and mature
neutrophils.
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.[citation needed]
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]
Genetics
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]
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]
G-CSF administration has been shown to attenuate the
telomere loss associated with chemotherapy.[16]
Use in drug-induced neutropenia
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.[17][18]
The FDA approved the first
biosimilar of Neulasta in June 2018. It is made by
Mylan and sold as Fulphila.[23]
Pharmaceutical variants
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]
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]
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1gnc: STRUCTURE AND DYNAMICS OF THE HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR DETERMINED BY NMR SPECTROSCOPY. LOOP MOBILITY IN A FOUR-HELIX-BUNDLE PROTEIN
1pgr: 2:2 COMPLEX OF G-CSF WITH ITS RECEPTOR
1rhg: THE STRUCTURE OF GRANULOCYTE-COLONY-STIMULATING FACTOR AND ITS RELATIONSHIP TO THOSE OF OTHER GROWTH FACTORS
2d9q: Crystal Structure of the Human GCSF-Receptor Signaling Complex