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Granulocyte-colony stimulating factor

From Academic Kids

Granulocyte-Colony Stimulating Factor (G-CSF) is a glycoprotein, growth factor or cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes. It also stimulates the survival, proliferation, differentiation and function of neutrophil granulocyte progenitor cells and mature neutrophils.

G-CSF is also known as Colony-Stimulating Factor 3 (CSF 3).

G-CSF should not be confused with granulocyte macrophage colony stimulating factor (GM-CSF), which is a distinctly different haemopoietic growth factor.

Contents

Biological function

G-CSF is produced by endothelium, macrophages and a number of other immune cells. The natural human glycoprotein exists in two forms of a 174 and 180 amino acid-long protein of molecular weight 19,600 grams/mole. The more abundant and more active 174 amino acid form has been used in the development of pharmaceutical products by recombinant DNA technology.

Mouse granulocyte colony stimulating factor (G-CSF) was first recognised and purified in Australia in 1983, and the human form was cloned by groups from Japan and the U.S.A. in 1986.

The receptor, G-CSF-receptor, is present on precursor cells in the bone marrow that, in response to stimulation by G-CSF, proliferate and differentiate into mature granulocytes.

Genetics

The gene for G-CSF is located on chromosome 17, locus q11.2-q12. Nagata et al. (1986) found that the GCSF gene has 4 introns and that 2 different 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.

Therapeutic use

G-CSF stimulates the production of white blood cells. In oncology and hematology, a recombinant form of G-CSF is used to accelerate recovery from neutropenia. Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cells, making patients prone for infections and sepsis.

The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim. The structure of filgrastim differs slightly from 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 (polyethylene glycol) form has a much longer half-life, reducing the necessity of daily injections. Recombinant G-CSF is also marketed under the names "Leukine" and "Sargramostim".

Another form of recombinant human G-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.

Reference

  • Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, et al. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 1986;319:415-8. PMID 3484805.

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