Granulocyte colony-stimulating factor

Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a is_associated_with::glycoprotein that stimulates the is_associated_with::bone marrow to produce is_associated_with::granulocytes and is_associated_with::stem cells and release them into the is_associated_with::bloodstream. Functionally, it is a is_associated_with::cytokine and is_associated_with::hormone, a type of is_associated_with::colony-stimulating factor, and is produced by a number of different tissues. The pharmaceutical analogs of naturally occurring G-CSF are called is_associated_with::filgrastim and is_associated_with::lenograstim.

G-CSF also stimulates the survival, proliferation, differentiation, and function of is_associated_with::neutrophil precursors and mature is_associated_with::neutrophils. G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras/is_associated_with::mitogen-activated protein kinase (MAPK) and is_associated_with::phosphatidylinositol 3-kinase (PI3K)/is_associated_with::protein kinase B (Akt) signal transduction pathway.

Discovery
Mouse granulocyte-colony stimulating factor (G-CSF) was first recognised and purified in is_associated_with::Walter and Eliza Hall Institute, is_associated_with::Australia in 1983, and the human form was cloned by groups from is_associated_with::Japan and is_associated_with::Germany/is_associated_with::United States in 1986.

Biological function
G-CSF is produced by is_associated_with::endothelium, is_associated_with::macrophages, and a number of other immune cells. The natural human glycoprotein exists in two forms, a 174- and 177-amino-acid-long is_associated_with::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 is_associated_with::recombinant DNA (rDNA) technology.

The G-CSF-receptor is present on precursor cells in the is_associated_with::bone marrow, and, in response to stimulation by G-CSF, initiates proliferation and differentiation into mature is_associated_with::granulocytes. G-CSF is also a potent inducer of HSCs 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.

Beside the effect on the hematopoietic system, 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 is_associated_with::neurogenesis, to increase the is_associated_with::neuroplasticity and to counteract is_associated_with::apoptosis. These properties are currently under investigations for the development of treatments of neurological diseases such as is_associated_with::cerebral ischemia.

Genetics
The gene for G-CSF is located on is_associated_with::chromosome 17, locus q11.2-q12. Nagata et al. found that the GCSF gene has 4 is_associated_with::introns, and that 2 different is_associated_with::polypeptides are synthesized from the same gene by differential splicing of mRNA.

The 2 polypeptides differ by the presence or absence of 3 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 is_associated_with::G-CSF factor stem-loop destabilising element.

Therapeutic use
G-CSF stimulates the production of granulocytes, a type of white blood cell. In is_associated_with::oncology and is_associated_with::hematology, a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery from is_associated_with::neutropenia after is_associated_with::chemotherapy, allowing higher-intensity treatment regimens. Chemotherapy can cause is_associated_with::myelosuppression and unacceptably low levels of is_associated_with::white blood cells, making patients susceptible to is_associated_with::infections and is_associated_with::sepsis.It is administered to oncology patients via subcutaneous or intravenous routes.

G-CSF is also used to increase the number of is_associated_with::hematopoietic stem cells in the blood of the donor before collection by is_associated_with::leukapheresis for use in is_associated_with::hematopoietic stem cell transplantation. For this purpose, G-CSF appears to be safe in is_associated_with::pregnancy during is_associated_with::implantation as well as during the second and third is_associated_with::trimesters. is_associated_with::Breastfeeding should be withheld for 3 days after CSF administration to allow for clearance of it from the milk.

G-CSF may also be given to the receiver in hematopoietic stem cell transplantation, to compensate for is_associated_with::conditioning regimens.

is_associated_with::Itescu 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.

A is_associated_with::Washington University School of Medicine study in mice has shown that G-CSF may decrease is_associated_with::bone mineral density.

Due to its neuroprotective properties, G-CSF is currently under investigation for is_associated_with::cerebral ischemia in a clinical phase IIb and several clinical pilot studies are published for other neurological disease such as is_associated_with::amyotrophic lateral sclerosis.

is_associated_with::Sweet's syndrome is a known side effect of using this drug.

It was first marketed by is_associated_with::Amgen with the brand name is_associated_with::Neupogen. Several bio-generic versions are now also available in markets such as Europe and Australia.

The recombinant human G-CSF synthesised in an is_associated_with::E. coli expression system is called is_associated_with::filgrastim. The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim. Filgrastim (Neupogen) and PEG-filgrastim (Neulasta) are two commercially-available forms of rhG-CSF (recombinant human G-CSF). The PEG (is_associated_with::polyethylene glycol) form has a much longer is_associated_with::half-life, reducing the necessity of daily injections.

Another form of recombinant human G-CSF called is_associated_with::lenograstim is synthesised in is_associated_with::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.

G-CSF when given early after exposure to radiation may improve white blood cell counts, and is stockpiled for use in radiation incidents.

People who have been administered colony-stimulating factors do not have a higher risk of is_associated_with::leukemia than people who have not.