G-CSF

Granulocyte colony-stimulating factor
	Ribbon model of the G-CSF trimer according to PDB 1RHG
	Existing structural data : 1cd9 , 1gnc , 1pgr , 1rhg , 2d9q
Properties of human protein
Mass / length primary structure	174 amino acids; 19.06 kDa
Isoforms	2
Identifier
Gene names	CSF3 ; G-CSF; GCSF; MGC45931
External IDs	OMIM : 138970 ; UniProt : P09919 ; MGI : 1339751 ; CAS number : 143011-72-7; (208265-92-3);
Drug information
ATC code	L03 AA02 L03 AA10 L03 AA13; ;
DrugBank	DB00099
Occurrence
Homology family	HBG005411
Parent taxon	Amniotes
	Orthologue

The granulocyte colony-stimulating factor (Engl. Granulocyte colony stimulating factor , G-CSF ) is a peptide hormone that as a cytokine , among others in inflammation is secreted by the body and the formation of granulocyte stimulating.

structure

The human glycoprotein consists of 174 amino acids , is glycosylated on the hydroxyl group of threonine 133 and has a molecular mass of 19.6 kDa. The glycosylation makes up about 4% of the total weight and consists of α-N-acetyl-neuraminic acid , β-galactose and N-acetyl-galactosamine. The glycosylation of G-CSF plays an essential role in the stability of the protein and in the stimulation of certain functions of the neutrophil granulocytes. Another essential element of the secondary structure are two disulfide bridges . The human gene for G-CSF is located on chromosome 17 in the gene locus q11.2-q12.

Biological function

G-CSF stimulates the survival and proliferation of immature progenitor cells of the haematopoietic system (pre-CFU) and determined progenitor cells for neutrophils (CFU-GM). G-CSF is given as a drug when, due to chemotherapy in cancer, the number of certain white blood cells (neutrophil granulocytes) threatens to drop to too low values, thereby increasing the risk of infections . In most cases, G-CSF is given prophylactically before the values have dropped too far. In the dosage that is achieved when given as a drug, G-CSF also shortens the development time from the progenitor cells to the mature neutrophil granulocytes from approx. 7 to 1.5 days.

Furthermore, G-CSF also acts on the mature neutrophil granulocytes. These cells also have G-CSF receptors. These cells are activated by G-CSF and chemotactically find their way to the sources of infection, where they then ingest and kill the bacteria. Glycosylation could be important for these functions of the neutrophils . The process of killing bacteria is also increased by G-CSF by increasing the superoxide production in the cells.

Another effect of G-CSF affects the haematopoietic (blood-forming) progenitor cells. Here G-CSF causes the cells to detach from their surroundings in the bone marrow . For this reason, after the administration of G-CSF, these precursor cells are partially released from the bone marrow into the peripheral blood and can be detected here. This effect is exploited by giving G-CSF to patients who are to receive high-dose chemotherapy or to healthy blood stem cell donors, and then the precursor cells can be collected from the peripheral blood. This collection process is called apheresis . After the high-dose chemotherapy, the patients either receive their own blood stem cells back (autologous transplantation) or the blood stem cells from a donor who matches the tissue characteristics (allogeneic transplantation). This peripheral blood stem cell transplant , made possible by the administration of G-CSF and apheresis, has largely replaced bone marrow transplantation.

Medicinal substances

As a medicinal substance, G-CSF is produced recombinantly either from CHO cells (lenograstim) or from E. coli (filgrastim). The amino acid sequence of filgrastim and lenograstim is identical, the newer lenograstim is also glycosylated at position 133 - according to the natural model. In addition, G-CSF also exists in PEGylated form ( lipegfilgrastim and pegfilgrastim ).

According to the current state of research, the drug causes itself

Reduce the infectious side effects of chemotherapy ( cancer treatment )

the neutropenia can be treated by permanent substitution of the missing granulocytes

Detach stem cells from the bone marrow and get into the peripheral blood ( stem cell transplant )

Side effects

Common side effects of G-CSF include bone and muscle pain as well as various non-specific complaints ( nausea , vomiting , diarrhea , loss of appetite , inflammation of the mucous membranes, hair loss , laboratory changes).

Rare side effects include lung infiltrates with cough , fever and shortness of breath up to Acute Respiratory Distress Syndrome (ARDS), enlargement of the spleen up to rupture of the spleen , and leukocytosis .

An American study also warns against the use in patients with sickle cell anemia , since severe side effects up to multiple organ failure seem to be common here.

The US National Marrow Donor Program annually reviews American bone marrow donors treated with filgrastim . In a cohort of 4015 donors whose G-CSF treatment was over between one and nine years, no increased incidence of cancer has so far been found. No leukemia cases were found in this cohort. This is recognized in reviews, but it is pointed out that in order to find a ten-fold increased risk, more than 2000 donors would have to be observed over ten years.

In August 2013, the manufacturers of the drugs Neupogen pointed ^® and Neulasta ^® ( Amgen ) in a Red Hand Letter suggests that treatment with filgrastim / pegfilgrastim with the risk of capillary leak syndrome (capillary leak syndrome, CLS) in cancer patients and healthy donors connected is.

Trade names

Filgrastim: Biograstim, Filgrastim HEXAL, Leucita, Neupogen, Nivestim, Ratiograstim, Accofil
Lenograstim: Granocyte
Lipegfilgrastim: Lonquex
Pegfilgrastim: Neulasta, Pelmeg, Pelgraz, Ziextenzo

Web links

Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Filgrastim

literature

K. Welte et al .: Purification and biochemical characterization of human pluripotent hematopoetic colony-stimulating factor . In: Proc. Natl. Acad. Sci. USA , 82, 1985, pp. 1526-1530
LM Souza et al .: Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. In: Science , Vol. 232, No. 4746, pp. 61-65, PMID 2420009
G. Ehninger (ed.): New trends to G-CSF in oncology. Springer Verlag, 2008, ISBN 978-3-540-49123-1 .
D. Metcalf: The colony-stimulating factors and cancer . In: Nature Reviews Cancer , Volume 10, 2010, pp. 425-434

Individual evidence

↑ Bernd Mirko Majorek: Pretreatment of blood donors with G-CSF for preparative granulocyte apheresis . Dissertation, University of Giessen, 2010, DNB 1009515918 .

↑ UniProt P09919

↑ CP Hill et al .: The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors. (PDF; 956 kB) In: Proc. Natl. Acad. Sci. USA , Vol. 90, 1993, pp. 5167-5171, PMID 7685117 .

^ Journal of Chemotherapy , 1994 , last accessed January 1, 2010

↑ Karow, Lang-Roth: Pharmacology and Toxicology . 2008.

^ Courtney D. Fitzhugh, Matthew M. Hsieh, Charles D. Bolan, Carla Saenz, John F. Tisdale: Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium ?. In: Cytotherapy. 11, 2009, pp. 464-471, doi : 10.1080 / 14653240902849788 , PMC 2747259 (free full text).

^ Confer, Miller: Long-term safety of filgrastim (rhG-CSF) administration . In: British Journal of Hematology , 137 (1), 2007, pp. 76–80, PMC 1920544 (free full text)

↑ Tigue et al: Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project . In: Bone Marrow Transplant . No. 40 (3) , 2007, pp. 185-192 , PMID 17563736 .

↑ Rote-Hand-Brief from Amgen on August 26, 2013. (PDF; 324 KB) Retrieved on August 26, 2013 .

[1] Bernd Mirko Majorek: Pretreatment of blood donors with G-CSF for preparative granulocyte apheresis . Dissertation, University of Giessen, 2010, DNB 1009515918 .

[2] UniProt P09919

[3] CP Hill et al .: The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors. (PDF; 956 kB) In: Proc. Natl. Acad. Sci. USA , Vol. 90, 1993, pp. 5167-5171, PMID 7685117 .

[4] Journal of Chemotherapy , 1994 , last accessed January 1, 2010

[Karow,Lang-Roth-5] Karow, Lang-Roth: Pharmacology and Toxicology . 2008.

[6] Courtney D. Fitzhugh, Matthew M. Hsieh, Charles D. Bolan, Carla Saenz, John F. Tisdale: Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium ?. In: Cytotherapy. 11, 2009, pp. 464-471, doi : 10.1080 / 14653240902849788 , PMC 2747259 (free full text).

[7] Confer, Miller: Long-term safety of filgrastim (rhG-CSF) administration . In: British Journal of Hematology , 137 (1), 2007, pp. 76–80, PMC 1920544 (free full text)

[Tigue-8] Tigue et al: Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project . In: Bone Marrow Transplant . No. 40 (3) , 2007, pp. 185-192 , PMID 17563736 .

[9] Rote-Hand-Brief from Amgen on August 26, 2013. (PDF; 324 KB) Retrieved on August 26, 2013 .