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PubMed2001

The effect of macrophage-colony stimulating factor and other humoral factors (interleukin-1, -3, -6, and -11, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor) on human osteoclast formation from circulating cells.

Macrophage-colony stimulating factor (M-CSF) is an essential requirement for human osteoclast formation, but its effect on the proliferation and differentiation of circulating osteoclast precursor cells is unknown. Other growth factors and cytokines are also known to support/stimulate osteoclast formation from mouse marrow precursors, but it is not certain whether these factors similarly influence human osteoclast formation. In this study, human monocytes were cocultured with osteoblast-like UMR-106 cells on coverslips and dentine slices for up to 21 days in the presence of 1,25 dihydroxyvitamin D(3) (10(-7) mol/L), dexamethasone (10(-8) mol/L), and various concentrations of either M-CSF or other humoral factors (interleukin [IL]-1beta, IL-3, IL-6, and IL-11; tumor necrosis factor-alpha [TNF-alpha]; and granulocyte macrophage [GM]-CSF). The effect on osteoclast formation was assessed by tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor staining and lacunar bone resorption. The results of time-course and proliferation studies showed that M-CSF stimulated both the proliferative and differentiation stages of human osteoclast formation from circulating osteoclast precursors in a dose-dependent manner. A high concentration of M-CSF (100 ng/mL) did not inhibit osteoclast formation. IL-3 and GM-CSF were also capable of stimulating human osteoclast formation, although these growth factors were much less potent than M-CSF. IL-3- and GM-CSF-stimulated osteoclast formation was inhibited by an antibody specific for human M-CSF. Osteoclast formation and lacunar resorption was not seen when either TNF-alpha, IL-1beta, IL-6 (+ soluble IL-6 receptor), or IL-11 was substituted for M-CSF during coculture. These results confirm that M-CSF is essential for human osteoclast formation from circulating mononuclear precursors, and also shows that IL-3 and GM-CSF may support osteoclast differentiation via the stimulation of M-CSF production by human monocytes.

Adult↗
PubMed1996

Granulocyte colony-stimulating factor (G-CSF) increases neutrophil migration across vascular endothelium independent of an effect on adhesion: comparison with granulocyte-macrophage colony-stimulating factor (GM-CSF).

Granulocyte colony-stimulating factor (G-CSF) increases neutrophil counts, and enhances and primes many neutrophil functions, implicating a role for this growth factor in host defence. This study investigated whether G-CSF is able to directly influence the transendothelial migration of neutrophils, and how such effects might be related to other effects on neutrophil adhesive properties. G-CSF, like GM-CSF, increased surface levels of the adhesive receptor, CD11b/CD18, but down-regulated L-selectin expression on neutrophils. Unlike GM-CSF, however, G-CSF had no effect on neutrophil adhesion to endothelium. Despite the lack of effect on neutrophil adhesion, G-CSF was able to produce significant enhancement of neutrophil transmigration across unstimulated endothelium in vitro. When used at an optimal concentration of 100 ng/ml, G-CSF increased neutrophil migration to 217 +/- 19% of baseline levels (P < 0.001, n = 10). This effect was similar to that previously demonstrated for GM-CSF (which increased migration to 271 +/- 40%, P < 0.001, n = 12). G-CSF-induced transmigration, like GM-CSF induced migration, was independent of concentration gradients, suggesting that these are not simply chemotactic effects. G-CSF differs from GM-CSF, however, in that although GM-CSF inhibited neutrophil migration across IL-1-activated endothelium (33 +/- 8% inhibition, n = 6, P < 0.01), G-CSF had no effect on neutrophil migration across IL-1 activated endothelium. Hence G-CSF, despite having no effect on neutrophil adhesion to endothelium, is a powerful stimulator of transmigration, and, unlike GM-CSF, does not inhibit cell movement across inflamed endothelium. These results suggest that G-CSF is able to influence neutrophil recruitment into local infective sites, and, further, that G-CSF mobilized cells would be competent to migrate into tissues in response to inflammatory stimuli.

Cell Adhesion↗
PubMed1998

A combination of low-dose cyclophosphamide and colony-stimulating factors is more cost-effective than granulocyte-colony-stimulating factors alone in mobilizing peripheral blood stem and progenitor cells.

BACKGROUND: The use of peripheral blood progenitor cells (PBPCs) instead of autologous bone marrow leads to more rapid engraftment following high-dose chemotherapy. Mobilization regimens differ with respect to toxicity, efficiency, and cost. STUDY DESIGN AND METHODS: Two cohorts of patients with breast cancer received one of two mobilization regimens: granulocyte-colony-stimulating factor (G-CSF) at 10 micrograms per kg was given subcutaneously for 5 days, with leukapheresis begun on Day 6, or low-dose cyclophosphamide followed by sequential granulocyte-macrophage-CSF (GM-CSF) at 5 micrograms per kg for 5 days and by G-CSF at 10 micrograms per kg, with leukapheresis begun on Day 11. Results of CD34+ cell collection, engraftment, and costs of mobilization were determined. RESULTS: The combination chemotherapy and growth factor regimen was more efficient in mobilizing CD34+ cells. Sixty-six percent of patients reached a target 4 x 10(6) CD34+ cells per kg in a single leukapheresis session with the combination regimen, compared to 14 percent who received G-CSF alone (p < 0.01). The mean number of leukapheresis sessions required to reach a target of 4 x 10(6) CD34+ cells per kg was 1.3 for the combination regimen and 2.7 for the regimen of G-CSF alone (p < 0.01). One patient in the chemotherapy and growth factor group developed febrile neutropenia. Engraftment was similar in both cohorts of patients. The cost of mobilization, including all supplies and cryopreservation, was $7381 for the G-CSF regimen and $5508 for the chemotherapy regimen (p < 0.05). This reduction was attributed to the lower number of leukapheresis and cryopreservation sessions, which outweighed the slight increase in expense for chemotherapy and growth factor in the combination regimen. CONCLUSION: This combination mobilization regimen allowed the predictable and efficient collection of CD34+ cells from the peripheral blood in a limited number of leukapheresis sessions, which reduced the cost of mobilization by approximately 25 percent.

Adult↗
PubMed2006

A Bayesian meta-analysis of prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in children with cancer.

The purpose of this analysis was to examine the efficacy of prophylactic hematopoietic colony-stimulating factors (CSFs) in pediatric cancer and to describe how a Bayesian meta-analysis can be conducted and then modified to incorporate information not readily included in a frequentist meta-analysis. Three Bayesian models were developed. The simplest model used the same data as a published frequentist meta-analysis. The second model included data that could not easily be incorporated into the frequentist meta-analysis, including data from different courses of chemotherapy and continuous outcomes that did not report variance estimates. The third model examined the effect of CSF type (granulocyte CSF vs. granulocyte-macrophage CSF). Compared with the frequentist model, the Bayesian model with the most data suggested a greater benefit of CSFs, with a 3.2-day reduction in duration of parenteral antibiotics (95% credible interval: -7.1, 0.7) in the expanded Bayesian model compared with a 0.8-day (95% confidence interval: -2.3, 0.7) reduction in the frequentist model. Bayesian meta-analysis also suggested that, compared with granulocyte-macrophage CSF, granulocyte CSF was associated with a 4.8-day decrease in the duration of parenteral antibiotics. Bayesian meta-analysis can readily include information not easily incorporated in a frequentist meta-analysis. Some treatment effect estimates were larger by a clinically important amount when additional data contributed to the pooled estimate.

Bayes Theorem↗
PubMed1997

Dimerization of granulocyte-colony stimulating factor receptor: the Ig plus CRH construct of granulocyte-colony stimulating factor receptor forms a 2:2 complex with a ligand.

We have previously shown that the extracellular domain of granulocyte-colony stimulating factor receptor (soluble G-CSFR), prepared from CHO cell conditioned media, dimerizes upon binding its ligand, G-CSF. The most stable ligand-receptor complex occurs at a 2:2 stoichiometry, unlike the growth hormone and erythropoietin systems. In the latter cases, each ligand uses two sites to bring two receptors together. In this study, we have generated a truncated G-CSF receptor, known to be sufficient for high affinity ligand binding, which consists of an Ig-like domain and a cytokine receptor homology module. With an affinity purified receptor, sedimentation equilibrium experiments clearly demonstrated that this truncated form of the receptor behaves very similarly to the entire extracellular domain. The sedimentation equilibrium data are consistent with the model that the truncated receptor has a weak tendency to self-associate into a dimer in the absence of a ligand, this receptor-receptor interaction is enhanced by ligand binding, and the most stable complex occurs at a 2:2 stoichiometry. These results are very different from those described by others for various murine G-CSF receptor constructs from either Escherichia coli or insect expression systems.

Animals↗
PubMed1994

Mapping of human granulocyte-macrophage-colony-stimulating-factor domains interacting with the human granulocyte-macrophage-colony-stimulating-factor-receptor alpha-subunit.

The high-affinity granulocyte-macrophage-colony-stimulating-factor (GM-CSF) receptor (R) is composed of at least two subunits, termed alpha and beta. The alpha subunit is crucial for initiating ligand/receptor interaction and for ligand specificity. The experiments reported in this study sought to identify the domains of human (h)GM-CSF which are responsible for interaction with hGM-CSFR alpha. Anti-(human-GM-CSF) mAb were used as competitors in a 125I-GM-CSF receptor-binding assay on cells expressing the recombinant hGM-CSFR alpha chain. Inhibition of 125I-GM-CSF binding to the GM-CSFR alpha chain was demonstrated by mAb which mapped to the middle third of the third alpha helix (amino acids 78-83), the distal two-thirds of the third alpha helix and the initial 7 residues of the loop between the third and fourth helix (amino acids 78-94), and the extreme carboxy terminus. No inhibition of binding occured with an antibody whose domain begins in the first beta-pleated sheet (amino acids, 39-43), continues through the second helix (amino acids 55-64) and into the proximal third of the third helix (to amino acid 77). mAb which mapped to the distal half of the fourth helix and the carboxy-terminal tail (amino acids 110-127) increased the binding of 125I-GM-CSF to GM-CSFR alpha. Due to the known discontinous epitopes the possibility that the distal portion of the fourth helix contributes to binding cannot be eliminated. However, the domains of hGM-CSF most clearly involved in binding to the hGM-CSFR alpha are the distal two-thirds of the third alpha helix, the immediate downstream residues and the extreme carboxy terminus of hGM-CSF.

Animals↗
PubMed1998

Activity of voriconazole, a new triazole, combined with neutrophils or monocytes against Candida albicans: effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor.

The antifungal activity of voriconazole (VCZ) was tested against Candida albicans in the absence or presence of polymorphonuclear neutrophils (PMN) or monocytes. In some experiments, VCZ was compared to fluconazole (FCZ). On a weight basis, VCZ was 10-fold more efficacious than FCZ against C. albicans Sh27. Against an FCZ-resistant isolate, VCZ at 1 microg/ml produced the same fungistasis as FCZ at 20 microg/ml. VCZ at 0.1 microg/ml collaborated with PMN for enhanced killing to the same extent as FCZ at 1.0 microg/ml. Granulocyte-colony-stimulating factor (G-CSF) enhanced the candidacidal activity of PMN, and it increased the collaboration of PMN with VCZ for killing. Granulocyte-macrophage (GM)-CSF also significantly enhanced both the killing by PMN and the collaboration of PMN with VCZ for killing. VCZ collaborated with GM-CSF-activated monocytes [corrected] for enhanced killing of C. albicans Sh27, and GM-CSF increased this collaboration. Taken together, these data show that VCZ is more potent than FCZ against C. albicans isolates, alone and in collaboration with PMN or monocytes for enhanced killing. In addition, G-CSF- or GM-CSF-activated PMN and monocytes have enhanced collaboration with VCZ compared to that of unstimulated phagocytes with VCZ.

Antifungal Agents↗
PubMed1991

Modulation of neonatal rat myeloid kinetics resulting in peripheral neutrophilia by single pulse administration of Rh granulocyte-macrophage colony-stimulating factor and Rh granulocyte colony-stimulating factor.

Rh granulocyte-macrophage (GM) colony-stimulating factor (CSF) and rh granulocyte (G) CSF have been demonstrated to induce proliferation and maturation of myeloid stem cells and release of mature polymorphonucleocytes (PMNs) from human and animal adult bone marrows. Unfortunately, reduced bone marrow progenitor cells, neutrophil storage pool (NSP) depletion and peripheral neutropenia are characteristic of human and animal newborn bone marrows. We investigated the effect of administering intraperitoneal rhGM-CSF and rhG-CSF to Sprague-Dawley newborn rats (less than 36 h). Newborn rats treated with intraperitoneal CSF (3.0 micrograms/kg) demonstrated significant leukocytosis at 6 and 24 h: rhGM-CSF vs. control, WBC (10(3)/mm3), at 6 h, 8.0 +/- 0.5 vs 4.3 +/- 0.9 (p less than or equal to 0.003), and at 24 h, 7.7 +/- 1.7 vs. 3.8 +/- 0.2 (p less than or equal to 0.008); rhG-CSF vs. control WBC (10(3)/mm3) at 6 h, 6.6 +/- 1.2 vs 4.3 +/- 0.1 (p less than or equal to 0.03), and at 24 h, 8.1 +/- 0.2 vs. 3.75 +/- 0.2 (p less than or equal to 0.003). The absolute neutrophil count was also significantly elevated at 6 h following intraperitoneal CSF (3.0 micrograms/kg): RhGM-CSF vs. control 1,827 +/- 25 vs. 379 +/- 10 (p less than or equal to 0.001); rhG-CSF vs. control, 1,698 +/- 40 vs. 371 +/- 10.1 (p less than or equal to 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia.

The role of mutations of the granulocyte colony-stimulating factor receptor (G-CSFR) in the pathogenesis of severe congenital neutropenia (SCN) and the subsequent development of acute myeloid leukemia (AML) is controversial. Mice carrying a targeted mutation of their G-CSFR that reproduces the mutation found in a patient with SCN and AML have been generated. The mutant G-CSFR allele is expressed in a myeloid-specific fashion at levels comparable to the wild-type allele. Mice heterozygous or homozygous for this mutation have normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis is normal. However, in response to G-CSF treatment, these mice demonstrate a significantly greater fold increase in the level of circulating neutrophils. This effect appears to be due to increased neutrophil production as the absolute number of G-CSF-responsive progenitors in the bone marrow and their proliferation in response to G-CSF is increased. Furthermore, the in vitro survival and G-CSF-dependent suppression of apoptosis of mutant neutrophils are normal. Despite this evidence for a hyperproliferative response to G-CSF, no cases of AML have been detected to date. These data demonstrate that the G-CSFR mutation found in patients with SCN is not sufficient to induce an SCN phenotype or AML in mice.

Acute Disease↗
PubMed2001

Multipotent hematopoietic cell lines derived from C/EBPalpha(-/-) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation.

The transcription factor C/EBPalpha is an important mediator of granulocyte differentiation and regulates the expression of multiple granulocyte-specific genes including the granulocyte-colony-stimulating factor (G-CSF) receptor, neutrophil elastase, and myeloperoxidase. Indeed C/EBPalpha knockout mice display a profound block in granulocyte differentiation. To study this block in granulocytic differentiation in more detail, retroviral vector-mediated transduction of a dominant-negative retinoic acid receptor was used to establish hematopoietic growth factor-dependent, lympho-myeloid progenitor cell lines from the fetal livers of both the C/EBPalpha knockout animals (C/EBPalpha(-/-)) and their heterozygous littermates (C/EBPalpha(+/-)). Surprisingly, the C/EBPalpha(-/-) cell lines displayed significant spontaneous granulocytic differentiation, and this differentiation was markedly enhanced when the cells were stimulated with granulocyte macrophage (GM)-CSF. This GM-CSF-mediated differentiation was associated with the up-regulation of G-CSF receptor mRNA, and the combination of GM-CSF and G-CSF generated more than 95% mature neutrophils in the C/EBPalpha(-/-) cultures. The addition of all-trans retinoic acid also enhanced this granulocytic differentiation of the cultured C/EBPalpha(-/-) cells, indicating that the activated retinoic acid receptors can enhance granulocytic differentiation through a molecular pathway that is independent of C/EBPalpha. These studies clearly indicate that terminal granulocytic differentiation associated with the up-regulation of C/EBPalpha-responsive genes can occur in the absence of C/EBPalpha, and they indicate the existence of multiple independent molecular pathways potentially used by primitive hematopoietic precursors that can lead to the development of mature granulocytes.

Animals↗
PubMed2004

Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality. METHODS: We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included. RESULTS: The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P =.01), and a decrease in hospitalization length, with a weighted mean difference of -1.9 days (95% CI, -2.7 to -1.1 days; P <.00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P =.02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P =.02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, -4.3; 95% CI, -10.6 to 2.0 days; P =.2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P =.97). CONCLUSION: CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.

Adolescent↗
PubMed2006

Meta-analysis of randomized controlled trials of prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor after autologous and allogeneic stem cell transplantation.

PURPOSE: The primary objective of our meta-analysis was to determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) after hematopoietic autologous and allogeneic stem-cell transplantation (SCT) reduced documented infections. Our secondary objectives were to determine whether prophylactic CSFs affected other outcomes including parenteral antibiotic therapy duration, infection-related mortality, graft-versus-host disease (GVHD), or treatment-related mortality. METHODS: We included studies if there was random assignment between CSFs and placebo/no therapy and CSFs were given after SCT and before recovery of neutrophils. From 3,778 reviewed study articles, 34 were included based on predefined inclusion criteria. All analyses were conducted using a random effects model. RESULTS: CSFs reduced the risk of documented infections (relative risk [RR] 0.87; 95% CI, 0.76 to 1.00; P = .05) and duration of parenteral antibiotics (weighted mean difference, -1.39 days, 95% CI, -2.56 to -0.22; P = .02) but did not reduce infection-related mortality (RR, 0.76; 95% CI, 0.41 to 1.44; P = .4). CSFs did not increase grade 2 to 4 acute GVHD (RR, 1.03; 95% CI, 0.81 to 1.31; P = .8) or treatment-related mortality (RR, 1.00; 95% CI, 0.78 to 1.29; P = .98). CONCLUSION: CSFs were associated with a small reduction in the risk of documented infections but did not affect infection or treatment-related mortality.

Anti-Bacterial Agents↗
PubMed1994

In vitro and in vivo effects of granulocyte colony-stimulating factor on neutrophils in glycogen storage disease type 1B: granulocyte colony-stimulating factor therapy corrects the neutropenia and the defects in respiratory burst activity and Ca2+ mobilization.

Children with glycogen storage disease (GSD) type 1b are susceptible to recurrent bacterial infections and have chronic neutropenia accompanied by phagocytic cell dysfunction including decreased superoxide anion (O2-) generation, calcium (Ca2+) mobilization, and chemotactic activity. Granulocyte colony-stimulating factor (G-CSF), a cytokine that corrects neutropenia in other diseases, in vitro enhances f-Met-Leu-Phe-triggered neutrophil O2- generation. Short-term pretreatment (15 min) of GSD 1b neutrophils with G-CSF increased the rate of O2- production (p < 0.01); however, this rate was still significantly below the rate of O2- production in control neutrophils. Recombinant human G-CSF (5 micrograms/kg/d) was administered s.c. to a GSD 1b patient. Before treatment, absolute neutrophil counts were < 500/mm3. Two d after G-CSF administration, the absolute neutrophil counts increased to 1333 and remained in the normal range during a 12-mo follow-up period. In vivo, G-CSF therapy increased f-Met-Leu-Phe-stimulated O2- production to 52% of control after 1 mo, and by mo 4, O2- production reached control levels. Our previous studies (J Clin Invest 56:196-202, 1990) demonstrated that decreased O2- production in neutrophils was associated with impaired Ca2+ mobilization. In vivo administration of G-CSF increased f-Met-Leu-Phe-triggered Ca2+ mobilization by neutrophils to 43% of control by mo 1 of G-CSF therapy and to 93% of control by mo 4, thus paralleling the improvements in O2- generation. In contrast, G-CSF therapy had no effect on the defective neutrophil chemotaxis. In summary, G-CSF therapy produced a rapid increase in circulating neutrophils and a gradual correction of O2- production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor corrects macrophage deficiencies, but not osteopetrosis, in the colony-stimulating factor-1-deficient op/op mouse.

The op mutation in the mouse is in the coding region of the colony-stimulating factor-1 (CSF-1) gene, prevents formation of biologically active factor, and, thus, results in generalized macrophage deficiency and, in osteopetrosis, secondary to deficiency of osteoclasts. Although a few macrophages and osteoclasts are present in these mutants, it was not clear whether the inability of endogenous granulocyte-macrophage CSF (GM-CSF) to compensate for the absence of CSF-1 was due to the limitations of biological activity of this molecule or to its inability to reach respective target populations. In this study, we examined whether sc GM-CSF in large doses (20-40 micrograms/mouse.day) for 3 weeks would correct some or all of the deficiencies observed in mutant mice. All organ macrophage populations tested (liver, spleen, thymus, marrow, pleural, and peritoneal cavity) were significantly increased, reaching levels exceeding those observed in normal mice. Restoration of peritoneal and pleural macrophage populations by sc GM-CSF is of particular interest, because it was not previously observed in op/op mice treated with sc CSF-1. In contrast, there was no indication of increased bone resorption, no appearance of osteoclasts, and no tooth eruption in response to GM-CSF treatment. These data suggest that GM-CSF is able to compensate for the absence of CSF-1 during macrophage formation, but is unable to play a similar role in osteoclast differentiation.

Animals↗
PubMed2001

Granulocyte-Colony stimulating factor and macrophage-colony stimulating factor in patients with non-small-cell lung cancer.

We have investigated the serum level of granulocyte-colony stimulating factor (G-CSF) and macrophagecolony stimulating factor (M-CSF) in non-small-cell lung cancer (NSCLC), in relation to the control group and commonly accepted tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin fragment 19 (CYFRA 21-1). Additionally, we have defined the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and receiver-operating characteristics (ROC) curve of G-CSF and M-CSF. Serum levels of cytokines were measured in 61 patients with NSCLC and in 20 healthy subjects. G-CSF and M-CSF were determined using ELISA. CYFRA 21-1 was measured by radioimmunoassay and CEA by microparticle enzyme immunoassay. There were significant increases in the level of circulating G-CSF in the lung cancer patients compared to the control group. Moreover, the diagnostic sensitivity of G-CSF was higher (56%) than the sensitivity of CYFRA 21-1 (51%), but lower than the CEA sensitivity (62%). The diagnostic specificity of G-CSF was higher (70%) than the M-CSF specificity (40%) and the G-CSF predictive values were higher in relation to the predictive values of M-CSF. These results suggest a potential role of G-CSF as a tumor marker for NSCLC.

Adult↗
PubMed2005

Effects of a formulary change from granulocyte colony-stimulating factor to granulocyte-macrophage colony-stimulating factor on outcomes in patients treated with myelosuppressive chemotherapy.

STUDY OBJECTIVE: To evaluate the effects on efficacy and safety of a formulary change from granulocyte colony-stimulating factor (G-CSF) to granulocyte-macrophage CSF (GM-CSF). DESIGN: Retrospective chart review. SETTING: Single-center academic institution. PATIENTS: Fifty-six patients aged 18 years or older with breast cancer, lung cancer, melanoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma who developed neutropenia within 4 weeks after treatment with myelosuppressive chemotherapy and who had been given five or more doses of CSF as primary or secondary prophylaxis from January 1995-March 2002. Twenty-nine patients treated before January 2000 were given G-CSF; after the formulary change in January 2000, 27 patients were primarily given GM-CSF. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end point was time to an absolute neutrophil count of 1.5x10(3)/mm3 or greater after treatment with CSF. Second and third efficacy end points, respectively, were frequency of febrile neutropenia and effect of CSF treatment on schedule and dose intensity of subsequent chemotherapy cycles. Primary and secondary safety end points, respectively, were frequency of adverse events and use of resources used to manage these events. The time to neutrophil recovery was similar with G-CSF and GM-CSF. Febrile neutropenia was more common in the patients given GM-CSF. Chemotherapy dose delays also were more common in patients treated with GM-CSF, as was the frequency of fever. Use of resources (platelet and red blood cell transfusions, intravenous antibiotics, and hospitalizations) was greater in the patients treated with GM-CSF. CONCLUSION: The formulary change to GM-CSF was associated with a higher frequency of febrile neutropenia, resultant chemotherapy dose delays, more adverse events, and greater use of resources to manage the adverse events. These results suggest that G-CSF and GM-CSF are not therapeutically equivalent, with G-CSF having a superior safety and efficacy profile for the prevention of chemotherapy-induced neutropenic events.

Antineoplastic Agents↗
PubMed2000

Inhibition of granulocyte colony-stimulating factor-mediated myeloid maturation by low level expression of the differentiation-defective class IV granulocyte colony-stimulating factor receptor isoform.

In acute myeloid leukemia (AML), granulocyte colony-stimulating factor receptor (G-CSFR) proliferative and maturational signaling pathways are uncoupled. Seven human G-CSFR mRNA isoforms exist, named class I through class VII. The 183-amino acid cytosolic domain of the class I isoform provides all signaling activities. The class IV isoform is "differentiation defective" because the carboxy-terminal 87 amino acids are replaced with 34 amino acids of novel sequence. In more than 50% of AML samples, the class IV/class I G-CSFR mRNA ratio is aberrantly elevated compared to normal CD34(+) bone marrow cells. We hypothesized that the increased relative expression of class IV G-CSFR in AML uncouples proliferative and maturational G-CSFR signaling pathways. To test this, we transfected the G-CSF-responsive murine cell line 32Dcl3 with class IV G-CSFR cDNA. After 10 days of G-CSF stimulation, clones expressing class IV G-CSFR had greater percentages of myeloblasts and promyelocytes than controls (53% +/- 13% versus 3% +/- 2%). Differential counts over time demonstrated delayed G-CSF-driven maturation in 5 class IV-expressing clones, with 2 clones demonstrating a subpopulation that completely failed to differentiate. Heterologous class IV expression did not affect G-CSF-dependent proliferation. Class IV/murine G-CSFR mRNA ratios after 24 hours of G-CSF stimulation for 3 of the 5 clones (range, 0. 090 to 0.245; mean, 0.152 +/- 0.055) are within the range of class IV/class I mRNA ratios seen in patients with AML. This indicates that aberrantly increased relative class IV G-CSFR expression seen in AML can uncouple G-CSFR proliferative and maturational signaling pathways.

Animals↗
PubMedDate not supplied

Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L).

The levels of hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders were investigated using a variety of approaches. Firstly, serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and Flt3-ligand (Flt3L) were examined in acute leukemia patients with treatment-induced cytopenia and complicating bacterial infections. Increased serum levels of both G-CSF and Flt3-ligand (Flt3L) were detected when these patients developed therapy-induced leukopenia, whereas GM-CSF levels were low or undetectable. Development of complicating bacterial infections then increased the serum levels of both G- and GM-CSF, and the Flt3L levels remained high during the infections. Secondly, release of growth factors was characterized for clonogenic T cells that remained in the circulation of acute leukemia patients with chemotherapy-induced cytopenia. CD4(+) and CD8(+) T cells from these patients released high levels of GM-CSF, relatively low levels of IL-3 secretion having been detected, and only a minority of the clones released detectable amounts of Flt3L. Thus, circulating T cells may contribute to the high systemic growth factor levels in cytopenic patients. Thirdly, plasma levels of GM-CSF and interleukin-3 (IL-3) were examined in patients with malignant disorders who received chemotherapy plus G-CSF for stem cell mobilization. Increased levels of GM-CSF and Flt3L were detected both in the patients' plasma and in the stem cell grafts. Despite the increased growth factor levels in neutropenic patients with complicating infections, the occurrence of febrile neutropenia did not have a major impact on normal hematopoietic reconstitution (i.e. duration of treatment-induced neutropenia) after intensive chemotherapy for acute myelogenous leukemia.

Adolescent↗