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Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor
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Not to be confused with granulocyte-macrophage colony-stimulating factor.

CSF3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCSF3, C17orf33, CSF3OS, GCSF, colony stimulating factor 3
External IDsOMIM: 138970; MGI: 1339751; HomoloGene: 7677; GeneCards: CSF3; OMA:CSF3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1440

12985

Ensembl

ENSG00000108342

ENSMUSG00000038067

UniProt

P09919

P09920

RefSeq (mRNA)

NM_000759
NM_001178147
NM_172219
NM_172220

NM_009971

RefSeq (protein)

NP_000750
NP_001171618
NP_757373
NP_757374

NP_034101

Location (UCSC)Chr 17: 40.02 – 40.02 MbChr 11: 98.59 – 98.59 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.[5][6]

Functionally, it is a cytokine and hormone, a type of colony-stimulating factor, and is produced by a number of different tissues. The pharmaceutical analogs of naturally occurring G-CSF are called filgrastim and lenograstim.

G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils.

Biological function

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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.[7]

White blood cells
The G-CSF-receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates proliferation and differentiation into mature granulocytes. G-CSF stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway.[citation needed]
Hematopoietic System
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.[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 induce neurogenesis, to increase the neuroplasticity and to counteract apoptosis.[9][10] These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.[11]

Genetics

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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.[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]

It is thought that stability of the G-CSF mRNA is regulated by an RNA element called the G-CSF factor stem-loop destabilising element.[citation needed]

Medical use

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Chemotherapy-induced neutropenia

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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.[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]

A study in mice has shown that G-CSF may decrease bone mineral density.[17]

G-CSF administration has been shown to attenuate the telomere loss associated with chemotherapy.[18]

Use in drug-induced neutropenia

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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.[19][20]

Before blood donation

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G-CSF is also used to increase the number of hematopoietic stem cells in the blood of the donor before collection by leukapheresis for use in hematopoietic stem cell transplantation. For this purpose, G-CSF appears to be safe in pregnancy during implantation as well as during the second and third trimesters.[21] Breastfeeding should be withheld for three days after CSF administration to allow for clearance of it from the milk.[21] People who have been administered colony-stimulating factors do not have a higher risk of leukemia than people who have not.[21]

Stem cell transplants

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G-CSF may also be given to the receiver in hematopoietic stem cell transplantation, to compensate for conditioning regimens.[18]

Side effect

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The skin disease Sweet's syndrome is a known side effect of using this drug.[22]

History

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Two research teams independently identified mouse colony stimulating factors in the 1960s: Ray Bradley at University of Melbourne and Donald Metcalf at Walter and Eliza Hall Institute, from Australia, and Yasuo Ichikawa, Dov Pluznik and Leo Sachs at the Weizmann Institute of Science, Israel.[23][24][7] In 1980 Antony Burgess and Donald Metcalf discovered that mouse lung conditioned medium contained at least two different CSFs [25] - GM-CSF, which they had purified in 1977 and a G-CSF which stimulated the production of colonies of neutrophils.

In 1983, Donald Metcalf's research team, led by Nicos Nicola, isolated the murine cytokine from medium conditioned with lung tissue obtained from endotoxin-treated mice.[26][27][7]

In 1985, Karl Welte, Erich Platzer, Janice Gabrilove, Roland Mertelsmann and Malcolm Moore at the Memorial Sloan Kettering Cancer Center (MSK) purified human G-CSF produced by bladder cancer cell line 5637 from conditioned medium.[28][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 with Chugai Pharmaceutical Co. from Japan, and Lawrence Souza's team at Amgen in collaboration with Karl Welte's research team members from Germany and the USA.[12][30][7]

Pharmaceutical variants

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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]

The Food and Drugs Administration (FDA) first approved filgrastim on February 20, 1991 marketed by Amgen with the brand name Neupogen.[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 with febrile neutropenia with fever.[31]

Several bio-generic versions are now also available in markets such as Europe and Australia. Filgrastim (Neupogen) and PEG-filgrastim (Neulasta), or pegylated form of filgratim, are two commercially available forms of rhG-CSF. The pegylated form of filgratim form has a much longer half-life, reducing the necessity of daily injections.

The FDA approved the first biosimilar of Neulasta in June 2018. It is made by Mylan and sold as Fulphila.[32]

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.

In 2015, filgrastim was included on the WHO Model List of Essential Medicines, a list containing the medications considered to be most effective and safe to meet the most important needs in a health system.[33][34]

Research

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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, plus SDF (stromal cell-derived factor) directly to the heart.[37]

G-CSF has been shown to reduce inflammation, reduce amyloid beta burden, and reverse cognitive impairment in a mouse model of Alzheimer's disease.[38]

Due to its neuroprotective properties, G-CSF is currently under investigation for cerebral ischemia in a clinical phase IIb [39] and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis[40] A combination of human G-CSF and cord blood cells has been shown to reduce impairment from chronic traumatic brain injury in rats.[41]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Granulocyte colony-stimulating factor

View on Grokipedia
from Grokipedia
Granulocyte colony-stimulating factor (G-CSF), encoded by the CSF3 gene, is a pleiotropic that primarily regulates the production, differentiation, and function of in the . It binds to the granulocyte colony-stimulating factor receptor (GCSFR, encoded by CSF3R) on target cells, activating signaling pathways such as JAK/STAT to promote and enhance neutrophil survival, mobilization, and antimicrobial activity. Endogenously produced by monocytes, macrophages, fibroblasts, and endothelial cells, G-CSF plays a critical role in maintaining immune and responding to infections or inflammatory stimuli. In clinical practice, recombinant G-CSF (rhG-CSF), such as (Neupogen®), is widely used to treat and prevent , particularly following myelosuppressive , by rapidly increasing counts within days to reduce risk. It also facilitates peripheral blood mobilization for transplantation and supports recovery in conditions like severe chronic or . Common side effects include due to marrow expansion, with rare risks such as or potential leukemic transformation in predisposed patients, though overall it is well-tolerated. The discovery of G-CSF traces back to the 1960s with early studies on colony-stimulating factors by researchers like Donald Metcalf, leading to its purification in 1983 and in the mid-1980s, which enabled recombinant production. Initial clinical trials in 1988 demonstrated its efficacy in boosting counts, resulting in FDA approval in 1991 for chemotherapy-induced and expanded indications thereafter, benefiting millions of patients worldwide. Ongoing research explores its broader therapeutic potential in non-hematologic applications, including and tissue repair.

Molecular Characteristics

Chemical Structure

Granulocyte colony-stimulating factor (G-CSF) is a that exists in two primary isoforms in humans due to of its mRNA. The predominant isoform, known as isoform B, consists of a mature polypeptide chain of 174 , while isoform A comprises 177 . Both forms share a high degree of sequence similarity, differing by the insertion of three (Val-Ser-Glu) in isoform A between residues 133 and 134 of isoform B. The molecular weight of the unglycosylated polypeptide backbone is approximately 19,600 g/mol for both isoforms. Glycosylation significantly influences the biophysical properties of G-CSF. The 174-amino-acid isoform (low-glycosylated form) features a single O-linked glycosylation site at threonine 133, where a Gal-GalNAc disaccharide may be further modified by up to two sialic acid residues, enhancing serum stability and resistance to proteolytic degradation by enzymes such as elastase. In contrast, the 177-amino-acid isoform (high-glycosylated form) has the O-linked site at threonine 136 and exhibits greater overall glycosylation occupancy, which contributes to improved in vivo half-life and biological potency compared to the low-glycosylated variant. Potential N-linked glycosylation sites exist at asparagine 62 and asparagine 145, but these are typically unoccupied in the natural protein, with glycosylation primarily limited to the O-linked modification. The presence of glycosylation shields critical residues, reducing aggregation and proteolysis, thereby amplifying the cytokine's therapeutic efficacy. The three-dimensional structure of human G-CSF, determined by , reveals a compact, predominantly helical fold characteristic of the cytokine family. It adopts an antiparallel four-α-helical bundle (up-up-down-down connectivity), with helices A (residues 11-41), B (71-95), C (102-124), and D (144-170) encompassing the core structure in the recombinant form analyzed. Short additional helical segments, including a 3₁₀-helix and an α-helix in the AB loop, contribute to the overall architecture, stabilized by two disulfide bonds (Cys36-Cys42 and Cys64-Cys74). Receptor binding occurs primarily through a cluster of charged and hydrophobic residues on helices A and C, including glutamate 19, 40, and 144, which form key interactions with the extracellular domain of the G-CSF receptor to initiate signaling. Structurally, G-CSF shares remarkable conservation with orthologs in other mammals, such as canine and bovine variants, all exhibiting the canonical four-α-helical bundle with near-identical connectivity and core pairings. Minor differences include an additional bond in bovine G-CSF (absent in ), yet the overall fold and receptor-binding interface remain highly similar, reflecting evolutionary preservation of function across . Sequence identity between and murine G-CSF is about 73% at the level, supporting in biological assays.

Genetics

The CSF3 gene, which encodes granulocyte colony-stimulating factor (G-CSF), is located on the long arm of human chromosome 17 at the cytogenetic band 17q21.1, spanning genomic coordinates 40,015,361 to 40,017,816 on the GRCh38 reference assembly. This positioning places it within a region associated with hematopoietic regulation, though specific neighboring genes do not directly influence its core function. The CSF3 gene is compact, covering approximately 2.4 kb of genomic DNA and organized into four exons separated by three introns. Alternative splicing occurs primarily through the use of two alternative 5' splice donor sites near the end of exon 4, generating two mature mRNA transcripts that differ by the inclusion or exclusion of a 15-nucleotide sequence encoding three additional amino acids, though both retain full biological activity. Transcriptional regulation of CSF3 is tightly controlled by its proximal promoter region, which spans about 200-300 base pairs upstream of the transcription start site and includes consensus binding sites for key inflammatory transcription factors. Notably, p65 binding sites enable rapid induction of CSF3 expression in response to pro-inflammatory stimuli such as (LPS) or cytokines like IL-17A, facilitating production during or tissue damage. Additionally, binding elements in the promoter mediate synergistic activation with , allowing corticosteroids to enhance CSF3 transcription in airway cells under inflammatory conditions. Other factors, including C/EBP family members, contribute to basal and inducible expression in myeloid cells, ensuring context-specific upregulation during acute inflammation. Post-transcriptionally, CSF3 mRNA stability is regulated by elements in its 3' (3' UTR), particularly a stem-loop destabilizing element (SLDE) consisting of a single conserved stem-loop structure. This SLDE promotes rapid deadenylation of the poly(A) tail by enhancing the processivity of deadenylase enzymes, leading to mRNA decay and limiting G-CSF protein accumulation under non-inflammatory conditions. The element's activity is independent of AU-rich elements () also present in the 3' UTR, providing an additional layer of control that fine-tunes expression in response to cellular stress or signaling pathways like p38 MAPK inhibition, which can stabilize the transcript.

Physiological Role

Biological Functions

Granulocyte colony-stimulating factor (G-CSF) plays a central role in hematopoiesis by primarily stimulating the production and maturation of granulocytes, especially neutrophils, within the . It acts on hematopoietic cells to promote their proliferation and differentiation into mature neutrophils, ensuring a rapid response to infections or inflammatory conditions. This process is crucial for maintaining adequate neutrophil counts in circulation, which are essential for innate immune defense against pathogens. Beyond production, G-CSF enhances the survival, functional capabilities, and release of into the bloodstream. It prolongs neutrophil lifespan by inhibiting , boosts their phagocytic activity, and improves toward infection sites, thereby amplifying the inflammatory response. Additionally, G-CSF facilitates the mobilization of hematopoietic stem cells from the niche into peripheral blood, aiding in tissue repair and immune reconstitution during stress. G-CSF also exhibits neurotrophic effects in the , promoting and providing . It counteracts neuronal , stimulates the generation of new neurons particularly in the hippocampus, and mitigates , contributing to brain repair in response to injury. These actions highlight G-CSF's broader role beyond hematopoiesis in supporting neural plasticity and resilience. Endogenously, G-CSF is produced by various cells in response to or , including endothelial cells, macrophages, fibroblasts, and monocytes. This localized synthesis ensures targeted delivery to sites of need, such as the bone marrow stroma or inflamed tissues, where it coordinates immune and regenerative processes.

Mechanism of Action

Granulocyte colony-stimulating factor (G-CSF), also known as CSF3, exerts its effects by binding to its specific receptor, CSF3R, a member of the class I family expressed primarily on hematopoietic cells such as precursors and mature neutrophils. Upon binding, G-CSF induces the dimerization of monomeric CSF3R, leading to the formation of a 2:2 ligand-receptor complex that facilitates across the plasma membrane. This ligand-receptor interaction triggers the of intracellular signaling cascades, primarily through the association of CSF3R's cytoplasmic domains with non-receptor kinases. The primary signaling pathway activated is the /signal transducer and activator of transcription (JAK/STAT) pathway, where JAK1, JAK2, and TYK2 kinases phosphorylate specific residues on CSF3R, recruiting and activating and STAT5b (with being particularly crucial for proliferation). Phosphorylated STAT proteins dimerize, translocate to the nucleus, and induce transcription of target genes. Concurrently, G-CSF stimulates the /extracellular signal-regulated kinase (MAPK/ERK) pathway via RAS-RAF-MEK-ERK activation, promoting cell proliferation, and the / (PI3K/Akt) pathway, which enhances cell survival and inhibits . These pathways collectively drive differentiation and expansion. Downstream of these signals, G-CSF upregulates anti-apoptotic genes such as Bcl-xL and survivin via STAT3 and PI3K/Akt, preventing programmed cell death in target cells, while STAT5-mediated inhibition of the cyclin-dependent kinase inhibitor p21 facilitates cell cycle progression and proliferation. In the context of stem cell mobilization, G-CSF indirectly promotes the release of hematopoietic stem and progenitor cells from the bone marrow niche by activating neutrophils to secrete proteases, including matrix metalloproteinase-9 (MMP-9), neutrophil elastase, and cathepsin G. These enzymes cleave key retention molecules, such as stromal cell-derived factor-1 (SDF-1/CXCL12), its receptor CXCR4, and vascular cell adhesion molecule-1 (VCAM-1), thereby disrupting cell adhesion to the extracellular matrix and endothelium; additionally, G-CSF downregulates VCAM-1 expression on stromal and osteoblastic cells, further facilitating egress into the bloodstream.

Clinical Applications

Treatment of Neutropenia

Granulocyte colony-stimulating factor (G-CSF), available as recombinant forms such as and , serves as a primary therapeutic agent for managing chemotherapy-induced , a common complication of myelosuppressive cancer treatments that increases risk. It is indicated to shorten the duration and mitigate the severity of severe , defined as an (ANC) below 500/μL, thereby reducing the period of vulnerability to . Clinical evidence supports its prophylactic administration starting shortly after to stimulate production and recovery. Efficacy trials demonstrate that G-CSF prophylaxis significantly lowers the incidence of , a severe manifestation involving fever and , by approximately 40-50% compared to or no prophylaxis across various solid tumors and lymphomas. This reduction is attributed to accelerated ANC recovery, with meta-analyses of randomized controlled trials showing relative risks for ranging from 0.51 overall, indicating a consistent protective effect without increasing overall mortality. Such outcomes are particularly notable in regimens with intermediate to high myelotoxicity, where G-CSF enables of dose intensity while minimizing hospitalization and use. Major oncology guidelines, including those from the (NCCN) and the (ASCO), recommend primary prophylactic G-CSF for patients receiving regimens with a ≥20% risk of , based on regimen-specific data and patient factors like age or comorbidities. For high-risk settings, such as certain or protocols, prophylaxis is advised to prevent severe unless an alternative less toxic regimen is available. Secondary prophylaxis is also endorsed following a prior episode to support ongoing treatment cycles. Beyond chemotherapy, G-CSF is employed in drug-induced neutropenia from agents like clozapine, an associated with risk, to facilitate safe drug continuation by promoting recovery. Systematic reviews indicate that prophylactic or therapeutic G-CSF dosing can maintain ANC above critical thresholds in such cases, allowing rechallenge after prior neutropenic events without universal discontinuation. Similar applications extend to induced by other myelosuppressive drugs, where G-CSF aids in resolving profound cytopenias and reducing infection complications.

Stem Cell Mobilization and Other Uses

Granulocyte colony-stimulating factor (G-CSF) is widely employed to mobilize hematopoietic s from the into the peripheral blood, facilitating their collection for transplantation purposes. In autologous transplantation, typically used in patients with hematologic malignancies such as or , G-CSF administration following enhances the yield of + stem cells, leading to faster engraftment and reduced duration of post-transplant compared to harvesting alone. For allogeneic transplantation, G-CSF-mobilized peripheral blood stem cells (PBSCs) from healthy donors provide higher cell doses and quicker recovery, though they are associated with a modestly increased risk of chronic without altering overall survival rates. Often, G-CSF is combined with myelosuppressive , such as , to synergistically boost stem cell release by first proliferating progenitors in the before mobilization. In healthy donors undergoing PBSC collection for allogeneic transplantation, G-CSF pretreatment at doses of 10 μg/kg/day for 4-5 days significantly increases circulating + cell counts, typically achieving yields sufficient for transplantation in over 90% of cases with a single procedure. This approach has become the standard for adult donors, offering logistical advantages over aspiration while maintaining long-term donor safety, with no increased risk of observed in follow-up studies. Beyond transplantation, G-CSF serves as an adjunctive therapy in non-malignant hematologic disorders. In severe , it shortens the duration of when used alongside immunosuppressive treatments like , promoting multilineage hematopoietic recovery in responsive patients, though it does not alter the underlying disease course. For congenital neutropenias, such as Kostmann syndrome, chronic G-CSF administration at 5-6 μg/kg/day effectively elevates absolute neutrophil counts, reducing infection frequency and improving quality of life, but long-term use requires monitoring for progression to or in a small subset of patients. G-CSF also mitigates radiation-induced myelosuppression, particularly in scenarios of accidental or therapeutic overexposure. Administered at 10 μg/kg/day subcutaneously, it accelerates recovery and enhances survival in animal models of high-dose , forming the basis for its recommendation in radiological/nuclear incidents to counteract acute hematopoietic . Clinical guidelines endorse its prompt initiation post-exposure to reduce risk during the vulnerable pancytopenic phase. Regarding safety in pregnant healthy donors, limited case series indicate that G-CSF mobilization during the second or third trimester is generally well-tolerated, with no adverse fetal outcomes reported in small cohorts undergoing PBSC collection, though first-trimester use is avoided due to limited data. Placental transfer occurs, but short-term maternal and fetal monitoring shows no significant complications, supporting its cautious application when donor urgency outweighs risks.

Pharmacology and Administration

Pharmacokinetics

Granulocyte colony-stimulating factor (G-CSF), when administered exogenously as recombinant forms such as or , exhibits nonlinear pharmacokinetics influenced primarily by dose, concentration, and count. Clearance occurs through two main pathways: saturable receptor-mediated binding to neutrophils leading to internalization and degradation, and unspecific renal . This -dependent clearance results in slower elimination during , as fewer cells are available for binding, thereby prolonging exposure. Following subcutaneous injection, is rapidly absorbed, achieving peak plasma concentrations within 2 to 8 hours, with absolute of 60% to 70%. For example, doses of 3.45 mcg/kg and 11.5 mcg/kg yield maximum serum levels of approximately 4 ng/mL and 49 ng/mL, respectively. In contrast, demonstrates slower absorption due to , with time to peak concentration typically occurring 1 to 2 days post-injection. reduces renal clearance and protects against receptor-mediated elimination, extending systemic exposure. Filgrastim distributes primarily to the , where it exerts its effects on progenitors, with a of about 150 mL/kg following intravenous administration. shows similar distribution patterns, though its prolonged circulation leads to greater accumulation in target tissues over time. involves proteolytic degradation after receptor binding, with no significant hepatic involvement identified. The elimination of is approximately 3.5 hours in both healthy individuals and cancer patients, with clearance rates of 0.5 to 0.7 mL/minute/kg. Pegfilgrastim's is markedly longer, ranging from 15 to 80 hours after , due to reduced clearance from and self-regulating binding. demonstrate dose non-proportionality, as higher doses saturate receptor-mediated clearance, leading to increased area under the curve beyond linear expectations. In neutropenic states, clearance diminishes for both forms, enhancing duration of action until recovery.

Dosage and Administration

Granulocyte colony-stimulating factor (G-CSF), such as , is administered primarily via subcutaneous injection, which is the preferred route in most clinical settings for its convenience, outpatient suitability, and comparable efficacy to other methods. Intravenous routes, including short infusions over 15 to 30 minutes or continuous infusions, are alternatives used in inpatient settings or when rapid onset is needed, though they may result in higher peak plasma concentrations compared to subcutaneous delivery. For chemotherapy-induced neutropenia, the standard starting dose is 5 μg/kg per day as a single daily injection, initiated at least 24 hours after cytotoxic completion and not administered within 24 hours prior to the next chemotherapy cycle. Therapy continues daily until the post-nadir (ANC) reaches 10,000 cells/mm³, generally for up to 2 weeks, with consideration for dose escalation in 5 μg/kg increments if the ANC response is suboptimal after the first week. In mobilization for peripheral blood collection, the recommended dose is 10 μg/kg per day via subcutaneous injection, administered for at least 4 consecutive days prior to the first procedure and continued until the final , often totaling 4 to 5 days with collections on days 5 through 7 as needed. Dosing is discontinued if the count surpasses 100,000 cells/mm³ to prevent . Clinical monitoring requires a baseline (CBC) and platelet count prior to initiation. For neutropenia treatment, serial CBCs and platelet counts are performed at least twice weekly to guide duration and adjustments based on ANC recovery; for mobilization, counts are evaluated after 4 days of dosing. All doses are calculated based on actual body weight, with practical rounding to available prefilled sizes (e.g., 300 mcg/0.5 mL or 480 mcg/0.8 mL), based on the calculated weight-based dose to facilitate administration.

Adverse Effects

Common Side Effects

The most common of granulocyte colony-stimulating factor (G-CSF) therapy is musculoskeletal pain, often manifesting as , which affects 20-30% of patients receiving prophylactic doses such as . This pain typically arises due to rapid expansion and is usually mild to moderate in severity, resolving after discontinuation of treatment. It can be effectively managed with analgesics, including acetaminophen or nonsteroidal anti-inflammatory drugs, in the majority of cases. Headache and are also frequently observed side effects during G-CSF administration, reported in approximately 10-20% of patients across various indications. Injection-site reactions, such as local , swelling, pain, or pruritus, occur commonly and are generally self-limiting following . Transient , an elevation in count, is a predictable and usually benign response to G-CSF, observed in most patients as production increases, though regular monitoring is essential to avoid excessive rises. In stem cell mobilization protocols, develops in nearly all healthy donors due to splenic sequestration of mobilized hematopoietic cells, with mean size increases of approximately 14%, though up to 50% in some cases, and resolving post-apheresis.

Rare and Serious Effects

While granulocyte colony-stimulating factor (G-CSF) therapy is generally well-tolerated, rare but serious adverse effects can occur, particularly in patients undergoing mobilization or recovery. , also known as acute , has been reported as a drug-induced complication following G-CSF administration, characterized by sudden onset of fever, tender erythematous plaques or nodules, and neutrophilic infiltration of the skin without . This condition is thought to arise from G-CSF's enhancement of activity and reduced , leading to localized inflammation. Cases are infrequent, often resolving with discontinuation of G-CSF and supportive care such as corticosteroids. Pulmonary complications, including acute respiratory distress syndrome (ARDS), represent another rare but life-threatening risk associated with G-CSF, typically emerging during the recovery phase from when counts surge. ARDS in this context may result from excessive activation and sequestration in the s, causing acute lung injury with , bilateral infiltrates, and potential progression to . Documented cases highlight the need for vigilant monitoring of respiratory status in at-risk patients, with management involving and G-CSF withdrawal. Although has been linked to disruptions in colony-stimulating factor signaling, direct causation by G-CSF remains unsubstantiated in clinical reports. Splenic rupture is an uncommon yet severe complication of G-CSF use, particularly during peripheral blood stem cell mobilization, where rapid from increases rupture risk. This atraumatic event can present with , hemodynamic instability, and , necessitating urgent in severe instances. The incidence is low, estimated at less than 0.1% in mobilized donors, but underscores the importance of counseling patients on symptoms like left upper quadrant pain. In predisposed individuals, such as those with congenital or underlying myelodysplastic syndromes (MDS), G-CSF therapy carries a rare risk of disease progression to MDS or (AML). This association may stem from G-CSF's promotion of clonal expansion in genetically altered hematopoietic cells, though large-scale studies indicate no significant increase in overall AML risk among non-predisposed patients receiving short-term therapy. Long-term follow-up is recommended for high-risk groups to detect cytogenetic abnormalities early.

History and Development

Discovery

The discovery of granulocyte colony-stimulating factor (G-CSF) originated from early investigations into the regulation of hematopoiesis in the 1960s. In 1966, researchers T.R. Bradley and Donald Metcalf at the Walter and Eliza Hall Institute in demonstrated the growth of cells, observing the formation of and colonies in semi-solid cultures stimulated by conditioned medium from lungs or cells. This seminal work established the existence of humoral factors capable of inducing colony formation from progenitors, laying the foundation for identifying specific colony-stimulating factors (CSFs). Independently, studies by Ichikawa, Pluznik, and Sachs around the same time confirmed the control of and colony development, highlighting the role of such factors in directing differentiation. Building on these observations, efforts in the and focused on purifying and characterizing individual CSFs. In 1977, Antony Burgess and Donald Metcalf achieved the first purification of a CSF from mouse lung-conditioned medium, initially identified as supporting -macrophage colony formation. Richard Stanley, collaborating with Metcalf, contributed to early purification strategies for macrophage-specific CSFs during this period. By 1983, Nicola, Metcalf, and colleagues purified a distinct factor from mouse lung-conditioned medium to homogeneity, naming it colony-stimulating factor (G-CSF) based on its selective stimulation of pure colonies from bone marrow progenitors. This purification, yielding a of approximately 25 kDa, confirmed G-CSF's role in promoting the proliferation and differentiation of committed precursors. The molecular characterization of G-CSF advanced rapidly in the mid-1980s. In 1986, Shozo Nagata and colleagues at Kirin Brewery (in collaboration with emerging biotech efforts) cloned the human G-CSF cDNA from a library derived from squamous cells, using probes based on partial sequences of the purified protein. This cloning revealed the gene's structure on chromosome 17 and enabled expression in mammalian cells, demonstrating that recombinant human G-CSF potently induced granulocyte colony formation from human progenitors , mirroring the native factor's activity. These findings solidified G-CSF as a key regulator of , distinct from other CSFs like GM-CSF.

Pharmaceutical Approvals

The first clinical trials of recombinant human granulocyte colony-stimulating factor (G-CSF), specifically , were initiated in 1988 for patients undergoing , demonstrating its potential to accelerate recovery and reduce risk in small cell cases. These early phase I and II studies laid the groundwork for larger evaluations, confirming safety and efficacy in mitigating chemotherapy-induced without significant toxicity. Pivotal phase III trials in the late and early provided robust evidence supporting regulatory approval. In a multicenter, randomized, double-blind study involving patients with small-cell lung cancer receiving , , and , administration reduced the median duration of severe (absolute neutrophil count <0.5 × 10^9/L) from 6 days to 1 day and the incidence of from 77% to 40%. Similar phase III results across diverse regimens showed consistent reductions in neutropenia duration by approximately 3 to 5 days, alongside decreased hospitalization and use, establishing 's role in supportive cancer care. The U.S. (FDA) granted approval for (Neupogen) on February 20, 1991, as the first recombinant G-CSF for reducing the incidence of infection in patients with nonmyeloid malignancies receiving myelosuppressive associated with severe . The (EMA), through its predecessor centralized procedures, similarly approved in 1991 for the same indication, facilitating its availability across European nations. Subsequent expansions included approvals for transplantation in 1994 and chronic in 1995 by the FDA. Filgrastim's global recognition culminated in its inclusion on the World Health Organization's Model List of in 2015, underscoring its cost-effective impact on reducing chemotherapy-related complications in resource-limited settings. This listing, based on updated guidelines from bodies like the , affirmed its essential status for primary prophylaxis in high-risk cases.

Variants and Research

Recombinant and Pegylated Forms

Recombinant forms of granulocyte colony-stimulating factor (G-CSF) have been developed to mimic the human protein for therapeutic use, primarily to stimulate production in patients undergoing . These forms are produced using technology and differ in their status, production methods, and pharmacokinetic profiles, which influence their clinical application. Filgrastim, marketed as Neupogen, is a non-glycosylated G-CSF consisting of 175 , including an N-terminal residue. It is manufactured by expressing the G-CSF in bacteria via technology, resulting in a protein that lacks the present in the native form. This production method yields a biologically active that effectively mobilizes neutrophils but has a short of approximately 3 to 4 hours, necessitating daily dosing. Pegfilgrastim, sold as Neulasta, is a pegylated derivative of designed to extend its duration of action. It is created by covalently attaching a 20-kDa monomethoxypolyethylene glycol (mPEG) to the N-terminal of filgrastim, which reduces renal clearance and prolongs the serum to 15 to 80 hours. This modification enables a convenient single-dose administration per cycle, improving patient compliance while maintaining equivalent neutrophil-stimulating efficacy to daily filgrastim. Lenograstim, available as Granocyte, represents a glycosylated recombinant form of G-CSF, produced by transfecting ovary (CHO) cells with the human G-CSF gene. This method allows for post-translational O-glycosylation at 133, making lenograstim structurally identical or highly similar to the endogenous protein, which includes , , and galactosamine residues. Compared to non-glycosylated , lenograstim exhibits higher potency in some neutrophil proliferation assays and similar clinical effectiveness in stimulating , though it also requires daily dosing due to a comparable short . Biosimilars of these recombinant G-CSF products have expanded treatment options by demonstrating high similarity to the reference biologics in terms of structure, purity, potency, , , and clinical efficacy and safety. Zarxio (filgrastim-sndz), approved by the FDA in 2015 as the first G-CSF , is highly similar to Neupogen and was shown in equivalence studies to produce comparable duration of severe and incidence of in patients receiving . Fulphila (pegfilgrastim-jmdb), approved in 2018 as a to Neulasta, underwent clinical trials confirming equivalent reduction in duration and similar safety profiles, including incidence. Additional approvals include Udenyca (pegfilgrastim-cbqv, 2018), Nyvepria (pegfilgrastim-apgf, 2020), Ziextenzo (pegfilgrastim-bmez, 2022), Fylnetra (pegfilgrastim-pbbk, 2022), and Stimufend (pegfilgrastim-fpgk, 2022) for , as well as Nivestym (filgrastim-aafi, 2018), Releuko (filgrastim-ayow, 2022), and Nypozi (filgrastim-txid, 2024) for . These have lowered treatment costs by up to 30-40% in some markets, enhancing access to G-CSF therapy without compromising outcomes, as evidenced by real-world studies showing non-inferiority in recovery rates.

Emerging Research and Applications

Research into granulocyte colony-stimulating factor (G-CSF) has expanded beyond its established hematopoietic roles, revealing potential neurotrophic effects that promote neuronal survival, anti-apoptosis, and in various neurological disorders. These properties arise from G-CSF's ability to cross the blood-brain barrier, activate anti-apoptotic pathways in neurons, and modulate inflammation, as demonstrated in preclinical models of brain injury and neurodegeneration. Clinical trials have explored these effects in , , and . For instance, a phase II randomized trial (NCT03656042) evaluated subcutaneous G-CSF in patients with mild-to-moderate , assessing cognitive outcomes and safety, with preliminary data suggesting tolerability. The trial was completed, but full efficacy results have not been published as of 2025. In stroke, multiple phase II studies, including a randomized controlled trial of G-CSF administration within seven days of acute ischemic stroke onset, showed trends toward improved functional outcomes and motor recovery compared to controls, though not statistically significant, attributed to enhanced and reduced infarct size. For , a phase II trial of intravenous low-dose G-CSF in early-stage patients showed neuroprotective benefits, including stabilized motor function as measured by Unified Parkinson's Disease Rating Scale scores over 12 months, building on phase I safety data from 2016. G-CSF has also been investigated as a radiation countermeasure. In 2015, the U.S. Food and Drug Administration approved filgrastim (Neupogen) for treating hematopoietic acute radiation syndrome in adults and pediatrics exposed to myelosuppressive radiation doses, based on non-human primate studies demonstrating accelerated neutrophil recovery and improved survival. Pegfilgrastim (Neulasta) received similar approval later that year for the same indication. Ongoing studies focus on mitigation strategies, including predictive modeling of survival benefits in radiation-exposed populations, which indicate that early G-CSF administration could reduce mortality by enhancing bone marrow recovery post-exposure. Emerging applications extend to , where G-CSF accelerates tissue repair by promoting , deposition, and immune cell recruitment. Preclinical rat models of hemorrhagic shock-induced wounds showed faster closure and reduced with subcutaneous G-CSF, while local injections in diabetic mice enhanced healing via increased production. In vaccine enhancement, G-CSF has demonstrated adjuvant potential by mobilizing dendritic cells and boosting antigen-specific immune responses; studies combining G-CSF with reported improved T-cell and antitumor immunity without significant added . For autoimmune diseases such as , preclinical evidence from experimental autoimmune models suggests G-CSF may reduce T-cell infiltration into the and attenuate disease severity, though clinical use requires caution due to reported flare risks in some patients. Despite these advances, challenges persist in G-CSF's broader applications, including the need for long-term beyond short-course administration, as prolonged use in neurological trials has shown good tolerability but limited follow-up on potential or off-target effects. Combination therapies, such as with for enhanced mobilization in investigational settings, have proven safe with no additional adverse events compared to G-CSF alone, though optimizing dosing to balance efficacy and remains an area of focus.

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