Granulocyte Colony-Stimulating Factor ; therapeutic use ; Humans ; Lymphoma ; drug therapy ; Recombinant Proteins ; therapeutic use ; Retrospective Studies

Granulocyte-Macrophage Colony-Stimulating Factor ; therapeutic use ; Humans ; Recombinant Fusion Proteins ; therapeutic use

Granulocyte colony-stimulating factor (G-CSF) is a kind of hematopoietic growth factor which is produced by monocytes, fibroblasts and endothelial cells. G-CSF acts on neutrophilic progenitor cells by binding to specific cell surface receptors, thereby stimulates proliferation, differentiation, commitment, and selected end-cell functional activation including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing and the increased expression of some functions associated with cell surface antigens. G-CSF is effective and safe for treatment of neutropenia. In this paper, structure of G-CSF and its mechanism, recent status of research on G-CSF, pharmacokinetics, clinical application, adverse effects and prospect of G-CSF are mainly reviewed.
Granulocyte Colony-Stimulating Factor ; pharmacokinetics ; pharmacology ; therapeutic use ; Hematopoiesis ; drug effects ; Humans

Granulocyte Colony-Stimulating Factor ; immunology ; pharmacology ; therapeutic use ; Humans ; Liver Failure ; immunology ; therapy

Hematopoietic Stem Cell Transplantation ; Granulocyte Colony-Stimulating Factor/therapeutic use* ; Immunoglobulins ; Granulocytes ; Hematopoietic Stem Cell Mobilization

OBJECTIVE: To observe the occurrence of immune dysfunction in children with aplastic anemia (AA) and the factors that may lead to immune dysfunction, analyze the relationship between the expression of granulocyte colony stimulating factor (G-CSF) and immune dysfunction. METHODS: A total of 34 children with AA treated in our hospital from December 2016 to September 2018 were selected. All the children received immunosuppressive therapy (IST) for 6 months. According to whether the children had immune dysfunction after 6 months of treatment, they were divided into occurrence group and non occurrence group. General information and laboratory indices were compared between the two groups, and serum G-CSF level was tested, the relationship between serum G-CSF level and immune dysfunction in AA children after treatment with IST was observed and analyzed. RESULTS: After treatment with IST for 6 months, 12 cases developed immune dysfunction (35.29%). Serum interferon (IFN)-γ level of the occurrence group was higher but G-CSF level was lower than those of the non occurrence group (P<0.05), while the difference of other baseline data was not statistically significant (P>0.05). Multiple regression analysis showed that overexpression of serum IFN-γ and low expression of G-CSF were both the influencing factors of immune dysfunction in AA children after IST treatment (OR>1, P<0.05). ROC curve was drawn, and the result showed that the area under the curve (AUC) of serum G-CSF level predicted the risk of immune dysfunction after IST was 0.843>0.80, when the index cut-off value was set at 6.614 pg/ml, the predictive value was ideal. CONCLUSION AA children have a higher risk of immune dysfunction after IST, which may be related to the low expression of serum G-CSF. The detection of serum G-CSF expression can be considered to predict the risk of immune dysfunction in AA children after IST, so as to guide early clinical intervention.
Anemia, Aplastic ; Antilymphocyte Serum/therapeutic use* ; Child ; Cyclosporine/therapeutic use* ; Granulocyte Colony-Stimulating Factor ; Humans ; Immunity ; Immunosuppressive Agents/therapeutic use*

The precise mechanism whereby granulocytes proliferate when haematopoietic colony stimulating factors (CSFs) are used in neutropenic cancer patients is poorly understood. The purpose of this study was to investigate whether these cytokines bring about leucocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase (DHFR). Blood samples were collected from 36 cancer patients (25 males and 11 females) with chemotherapy-induced neutropenia. One sample of blood from each patient was obtained before therapy either with CSF, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) or with placebo, and another one at the time of resolution of neutropenia. Peripheral blood leucocytes in these blood samples were counted, separated and lysed. From lysates, cytoplasmic samples were prepared and analyzed for active DHFR by a methotrexate-binding assay and for total immunoreactive DHFR by an enzyme linked immunosorbent assay. The increase in total leucocyte count (TLC) was most prominent (P < 0.005) in the CSF group and less so (P < 0.05) in the placebo group. The mean +/- SD concentration values of active DHFR before and after stimulation with GM-CSF found were to be 0.34 +/- 0.4 ng/mg protein and 0.99 +/- 0.82 ng/mg protein, respectively, and in the group treated with G-CSF, 0.24 +/- 0.32 ng/mg protein and 1.18 +/- 2.4 ng/mg protein, respectively. This increase in active DHFR after stimulation with CSF was statistically significant (P <0.05). Similarly, concentration values of immunoreactive but nonfunctional form of DHFR (IRE) were 110 +/- 97 ng/mg protein and 605 +/- 475 ng/mg protein before and after stimulation with GM-CSF, and 115 +/- 165 ng/mg protein and 1,054 +/- 1,095 ng/ mg protein before and after stimulation with G-CSF. This increase in concentration of IRE after stimulation with GM-CSF or G-CSF was statistically significant (P < 0.005). In the control group, there was an increase in the concentration of both active DHFR and IRE after treatment with placebo. However, this was not statistically significant. Resolution of neutropenia was quicker in the groups treated with CSF compared to the control group. Results of this study indicate that colony stimulating factors (G-CSF and GM-CSF) induce white cell proliferation by increasing the levels of multiple forms of DHFR.
Adolescence ; Adult ; Cell Division/drug effects ; Child ; Female ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Granulocyte Colony-Stimulating Factor/pharmacology* ; Granulocyte Colony-Stimulating Factor/adverse effects ; Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology* ; Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects ; Human ; Isoenzymes/metabolism ; Isoenzymes/biosynthesis ; Leukocyte Count ; Leukocytes/pathology ; Leukocytes/enzymology ; Leukocytes/drug effects ; Male ; Middle Age ; Neoplasms/enzymology ; Neoplasms/drug therapy ; Neoplasms/blood* ; Neutropenia/metabolism* ; Neutropenia/chemically induce ; Neutropenia/blood ; Tetrahydrofolate Dehydrogenase/metabolism* ; Tetrahydrofolate Dehydrogenase/biosynthesis

OBJECTIVETo testify whether absolute neutrophil count (ANC) response to preimmunosuppressive-therapy (pre-IST) granulocyte-stimulating factor (G-CSF) treatment could predict early response to IST in severe aplastic anemia (SAA).

METHODSClinical data and hematologic response of 125 SAA patients treated with antithymocyte globulin (r-ATG) combined with cyclosporine were retrospectively analyzed. Correlation of ANC response to pre-IST G-CSF treatment and early response to IST were statistically analyzed, and receiver operating characteristic (ROC) curve was used to estimate the value of increased ANC (∆ANC) in predicting early IST response.

RESULTSThe hematologic response (HR) rate to IST in ANC reponded patients was significantly higher than non-responded group (3-month HR 49.0% vs 28.9%, P=0.023; 6-month HR 61.2% vs 40.8%, P=0.026). With ∆ANC≥0.5×10⁹/L as cutoff level, the best point to predict early IST response was 10 days after G-CSF (d 10). Response of ANC to pre-IST G-CSF treatment at d 10 was among the independent factors of predicting 3-month (P=0.004), but not for 6-month response to IST. The overall 5-year survival rate was 92.8% and 69.5% in ANC responded and non-responed groups, respectively (P=0.025).

CONCLUSIONResponding to pre-IST G-CSF treatment reflected the residual bone marrow hematopoiesis, and could act as a convenient and practical predictor to early IST response as well as long-term survival in SAA.

Anemia, Aplastic ; drug therapy ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Humans ; Immunosuppressive Agents ; therapeutic use ; Neutrophils ; drug effects

OBJECTIVETo compare the efficacy and safety of two different regimens with recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with intensified immunosuppressive therapy (IIST) in severe aplastic anemia (SAA).

METHODSRetrospectively analyzed 176 SAA treated with IIST and rhG-CSF in our hospital from March 1994 to December 2007. Regimen A (Group A, n = 96), rhG-CSF 300 µg/d was initiated on day 31 after IIST and subcutaneously administered 1-3 days a week for 3 months. Regimen B (Group B, n = 80), rhG-CSF was initiated at 5 µg·kg(-1)·d(-1) before IIST until hematologic recovery.

RESULTS(1) The early response rate of Group B (67.5%) was significantly higher than that of Group A (37.5%) (P < 0.01), the interval from IIST to response in Group B was shorter than that in Group A. Moreover, infection-related deaths during first 4 months after IIST were significantly reduced in Group B (6.3%) when compared with Group A (16.7%) (P = 0.034). The cumulative incidence of survival at 4 years in Groups B [(77.7 ± 4.9)%] was also significantly higher than that in Group A [(57.2 ± 5.1)%] (P = 0.006). (2) With regard to 93 refractory patients with no response 4 months after IIST, rhG-CSF therapy was continued in Group B meanwhile stopped in Group A. There were no differences between two groups in terms of survival and the response rates (P = 0.288, 0.066), but there was an increasing risk of evolving into MDS/AML in Group B (22.3%) when compared with Group A (3.71%) (P = 0.023). (3) By multivariate analysis, the severity of disease (P = 0.010, RR = 1.922) and the early response (P < 0.01, RR = 5.749) were associated with the overall survival. Moreover, the number of days of rhG-CSF therapy was the only significant risk factor for SAA evolving into MDS/AML (P = 0.017, RR = 1.004).

CONCLUSIONSThe early initiation of rhG-CSF therapy with proper dose might contribute to a desirable early response and reduced infection-related death rate, but extended administration of rhG-CSF did not improve the long-term outcome of refractory SAA and may further facilitate the progression of SAA into MDS/AML.

Anemia, Aplastic ; therapy ; Follow-Up Studies ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Humans ; Immunosuppression ; Recombinant Proteins ; therapeutic use ; Retrospective Studies

BACKGROUNDGranulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent hematopoietic growth factor that both enhances the survival and drives the differentiation and proliferation of myeloid lineage cells. Recent studies have suggested that GM-CSF has a neuroprotective effect against cerebral ischemia injury, but the molecular mechanisms have been unclear. This study aimed to investigate the influences of a short-acting (half-life 3.5 hours) G-CSF and a long-acting (half-life 40 hours) pegylated G-CSF on the JNK signaling pathway after cerebral ischemia reperfusion.

METHODSA total of 52 Sprague-Dawley rats were randomly divided into four groups: a sham group (n = 4), a vehicle with saline (n = 16), a short-acting G-CSF treatment group (n = 16) and a long-acting G-CSF treatment group (n = 16). The cerebral ischemia reperfusion model was established for the sham group and G-CSF treatment groups by middle cerebral artery occlusion (MCAO). Five days post reperfusion, rats were sacrificed and the brains were removed. Changes in neurological function after cerebral ischemia reperfusion was evaluated according to Neurological Severity Score (NSS) and the lesion volume and infarct size were measured by 2,3,5-triphenyltetrazolium chloride staining. The numbers of apoptotic neurons in these ischemic areas: left cerebral cortex, striatum and hippocampus were calculated by TUNEL assay, and expression of JNK/P-JNK, c-jun/P-c-jun in these areas was detected by Western blotting.

RESULTSCompared with the saline vehicle group ((249.68±23.36) mm(3), (19.27±3.37)%), G-CSF-treated rats revealed a significant reduction in lesion volume (long-acting: (10.89±1.90)%, P < 0.01; short-acting G-CSF: (11.69±1.41)%, P < 0.01) and infarct size (long-acting: (170.53±18.47) mm3, P < 0.01; short-acting G-CSF: (180.74±16.93) mm3, P < 0.01) as well as less neuron functional damage (P < 0.01) and a smaller number of apoptotic neurons in ischemic areas (P < 0.01). The activity of P-JNK and P-c-jun in the cerebral ischemia reperfusion-damaged cortex and hippocampus was significantly decreased in all G-CSF-treated rats (P < 0.05). However, between the long-acting and short-acting G-CSF sets, there were no significant differences found in the activity of P-JNK and P-c-jun in the cortex, hippocampus and striate body (P > 0.05).

CONCLUSIONSHypodermic injection of 50 µg/kg G-CSF attenuated the damage caused by cerebral ischemia reperfusion in rats, which might be associated with down-regulated activation of the P-JNK and P-c-jun pathway after cerebral ischemia reperfusion. Long-acting G-CSF may be a novel choice for both clinical and basic research in treating cerebral ischemia.

Animals ; Brain Ischemia ; drug therapy ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Neuroprotective Agents ; therapeutic use ; Rats ; Rats, Sprague-Dawley