G-CSF is produced byendothelium,macrophages, and a number of otherimmune cells. The natural human glycoprotein exists in two forms, a 174- and 177-amino-acid-longprotein of molecular weight 19,600 grams permole. The more-abundant and more-active 174-amino acid form has been used in the development of pharmaceutical products byrecombinant DNA (rDNA) technology.[7]
G-CSF is also a potent inducer ofhematopoietic 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.[8]
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 induceneurogenesis, to increase theneuroplasticity and to counteractapoptosis.[9][10] These properties are currently under investigations for the development of treatments of neurological diseases such ascerebral ischemia.[11]
The gene for G-CSF is located onchromosome 17, locus q11.2-q12. Nagata et al. found that the GCSF gene has fourintrons, and that two differentpolypeptides are synthesized from the same gene by differential splicing of mRNA.[12]
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 causemyelosuppression and unacceptably low levels ofwhite blood cells (leukopenia), making patients susceptible toinfections andsepsis. G-CSF stimulates the production ofgranulocytes, a type of white blood cell. Inoncology andhematology, a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery and reduce mortality fromneutropenia afterchemotherapy, allowing higher-intensity treatment regimens.[13] It is administered to oncology patients via subcutaneous or intravenous routes.[14] 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.[15]
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.[16]
Neutropenia can be a severe side effect ofclozapine, anantipsychotic medication in the treatment ofschizophrenia. G-CSF can restore neutrophil count. Following a return to baseline after stopping the drug, it may sometimes be safelyrechallenged with the added use of G-CSF.[19][20]
In 1983, Donald Metcalf's research team, led byNicos Nicola, isolated the murine cytokine from medium conditioned with lung tissue obtained from endotoxin-treated mice.[26][27][7]
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).[29] 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 withChugai Pharmaceutical Co. fromJapan, andLawrence Souza's team atAmgen in collaboration with Karl Welte's research team members fromGermany and theUSA.[12][30][7]
Therecombinant human G-CSF (rhG-CSF) synthesised in anE. coli expression system is calledfilgrastim. The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim.[citation needed]
TheFood and Drugs Administration (FDA) first approved filgrastim on February 20, 1991 marketed byAmgen with the brand nameNeupogen.[31] It was initially approved to reduce the risk of infection in patients with non-myeloid malignancies who are taking myelosuppressive anti-cancer drugs associated withfebrile neutropenia with fever.[31]
Several bio-generic versions are now also available in markets such as Europe and Australia. Filgrastim (Neupogen) andPEG-filgrastim (Neulasta), orpegylated form of filgratim, are two commercially available forms of rhG-CSF. The pegylated form of filgratim form has a much longerhalf-life, reducing the necessity of daily injections.
The FDA approved the firstbiosimilar of Neulasta in June 2018. It is made byMylan and sold as Fulphila.[32]
Another form of rhG-CSF calledlenograstim is synthesised inChinese 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.[35][36]
Mesoblast planned in 2004 to use G-CSF to treat heart degeneration by injecting it into the blood-stream, plusSDF (stromal cell-derived factor) directly to the heart.[37]
Due to its neuroprotective properties, G-CSF is currently under investigation forcerebral ischemia in a clinical phase IIb[39] and several clinical pilot studies are published for other neurological disease such asamyotrophic lateral sclerosis[40] A combination of human G-CSF andcord blood cells has been shown to reduce impairment from chronic traumatic brain injury in rats.[41]
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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
