Efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor secondary prophylaxis in capecitabine combined with oxaliplatin (CapeOX) regimen in the treatment of colorectal cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2739432 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:CD34+ hematopoietic stem and progenitor cells were isolated immunomagnetically from patients with multiple myeloma during chemotherapy and G-CSF-induced mobilization. Patients received either unconjugated G-CSF (n=9) or polyethylenglykol (PEG)-conjugated G-CSF (n=7). From each patient only one sample was analyzed. Total RNA was extracted, reversely transcribed, in vitro transcribed and labelled and hybridized to Affymetrix HG Focus Arrays according to manufacturer's instructions. Following quality control and normalization 9 samples of G-CSF-mobilized CD34+ cells were compared with 7 samples of PEG-G-CSF-mobilized cells were compared by significance analysis of microarrays (SAM). The aim was to figure out transcriptional differences resulting from various pharmacokinetics of the same drug (G-CSF: fluctuating serum levels; PEG-G-CSF: continously high serum levels). Peripheral blood stem and progenitor cells (PBSC) are widely used for autologous and allogeneic hematopoietic stem cell transplantation. PBSC can be mobilized into the peripheral blood using cytokines, cytotoxic chemotherapy or a combination of both. Granulocyte colony stimulating factor (G-CSF) has become the most commonly administered cytokine for PBSC mobilization because of its high potency and lack of serious toxicity. Recently, a modified form of recombinant human G-CSF has been introduced. This new compound is pegylated G-CSF (Peg-G-CSF) which possesses a substantially longer half-life than the unconjugated drug because of its reduced renal excretion and therefore provides the basis for continuous G-CSF serum-levels after a single injection. The use of Peg-G-CSF in patients who had received a cytotoxic chemotherapy was accompanied by mobilization kinetics different from those observed in patients who had received unconjugated G-CSF. In particular, more rapid leukocyte recovery and occurrence of CD34-positive cells in the peripheral blood was seen. These findings are presumably related to the more even and continuously high serum level of G-CSF maintained by Peg-G-CSF. Using microarray technology and functional assays, we examined whether pegylation of G-CSF and its different pharmacokinetics results in addition to an earlier leucocyte recovery in transcriptional and functional changes in CD34+ cells obtained from patients who had received either G-CSF or Peg-G-CSF following a standard cytotoxic chemotherapy for PBSC mobilisation. CD34+ hematopoietic stem and progenitor cells were isolated immunomagnetically from patients with multiple myeloma during chemotherapy and G-CSF-induced mobilization. Patients received either unconjugated G-CSF (n=9) or polyethylenglykol (PEG)-conjugated G-CSF (n=7). Total RNA was extracted, reversely transcribed, in vitro transcribed and labelled and hybridized to Affymetrix HG Focus Arrays. Following quality control and normalization differentially expressed genes were identified by significance analysis of microarrays (SAM). Comparing both groups 339 genes were significantly differentially expressed (q value <5%; fold change > 1.2). Peg-G-CSF-mobilized CD34+ cells showed an expression pattern of more early progenitor cells as early stem cell markers such as HOX genes were higher expressed and differentiation-associated genes were lower expressed in comparison with G-CSF-mobilized cells. Moreover, Peg-G-CSF-mobilized CD34+ cells had a greater expression level of cell-cycle-promoting genes suggesting a greater cycle activity of these cells. In conclusion, despite the similar active drug component different pharmacokinetics of Peg-G-CSF and G-CSF result in distinct molecular phenotypes reflecting different functional characteristics.
2007-10-26 | E-GEOD-4688 | biostudies-arrayexpress
Project description:Peripheral blood stem and progenitor cells (PBSC) are widely used for autologous and allogeneic hematopoietic stem cell transplantation. PBSC can be mobilized into the peripheral blood using cytokines, cytotoxic chemotherapy or a combination of both. Granulocyte colony stimulating factor (G-CSF) has become the most commonly administered cytokine for PBSC mobilization because of its high potency and lack of serious toxicity. Recently, a modified form of recombinant human G-CSF has been introduced. This new compound is pegylated G-CSF (Peg-G-CSF) which possesses a substantially longer half-life than the unconjugated drug because of its reduced renal excretion and therefore provides the basis for continuous G-CSF serum-levels after a single injection. The use of Peg-G-CSF in patients who had received a cytotoxic chemotherapy was accompanied by mobilization kinetics different from those observed in patients who had received unconjugated G-CSF. In particular, more rapid leukocyte recovery and occurrence of CD34-positive cells in the peripheral blood was seen. These findings are presumably related to the more even and continuously high serum level of G-CSF maintained by Peg-G-CSF. Using microarray technology and functional assays, we examined whether pegylation of G-CSF and its different pharmacokinetics results in addition to an earlier leucocyte recovery in transcriptional and functional changes in CD34+ cells obtained from patients who had received either G-CSF or Peg-G-CSF following a standard cytotoxic chemotherapy for PBSC mobilisation. CD34+ hematopoietic stem and progenitor cells were isolated immunomagnetically from patients with multiple myeloma during chemotherapy and G-CSF-induced mobilization. Patients received either unconjugated G-CSF (n=9) or polyethylenglykol (PEG)-conjugated G-CSF (n=7). Total RNA was extracted, reversely transcribed, in vitro transcribed and labelled and hybridized to Affymetrix HG Focus Arrays. Following quality control and normalization differentially expressed genes were identified by significance analysis of microarrays (SAM). Comparing both groups 339 genes were significantly differentially expressed (q value <5%; fold change > 1.2). Peg-G-CSF-mobilized CD34+ cells showed an expression pattern of more early progenitor cells as early stem cell markers such as HOX genes were higher expressed and differentiation-associated genes were lower expressed in comparison with G-CSF-mobilized cells. Moreover, Peg-G-CSF-mobilized CD34+ cells had a greater expression level of cell-cycle-promoting genes suggesting a greater cycle activity of these cells. In conclusion, despite the similar active drug component different pharmacokinetics of Peg-G-CSF and G-CSF result in distinct molecular phenotypes reflecting different functional characteristics. Keywords: ordered
2006-05-03 | GSE4688 | GEO
Project description:This study tested the hypothesis that recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) enhances polymorphonuclear neutrophils (PMNs) via IL-1β to improve the prognosis of secondary infection in sepsis. The latter stage of sepsis is prone to induce immunosuppression, resulting in secondary fatal infections. rGM-CSF has become a way for sepsis-induced immunosuppression due to its immunomodulatory effect. However, the functional impact of GM-CSF on PMNs in sepsis remains obscure. This study aimed to study the role of rGM-CSF on the bactericidal ability of PMNs in septic mice, assessing its effect on the prognosis of secondary pneumonia, and explore the mechanism of rGM-CSF by intervening PMNs in patients with sepsis. The C57BL/6J sepsis mouse model was induced by cecal ligation and puncture (CLP). rmGM-CSF was used in vivo when mice developed immunosuppression, which was characterized by abnormal bactericidal function of PMNs in peripheral blood. rmGM-CSF improved the prognosis of secondary pneumonia and reversed the function of PMNs. PMNs isolated by Percoll from septic patients were treated by rhGM-CSF in vitro. The expression of CD11b, reactive oxygen species (ROS), phagocytosis and neutrophil extracellular traps (NETs) release in PMNs were enhanced by rhGM-CSF treatments. Whole-transcriptomic sequencing of mouse PMNs indicated that recombinant GM-CSF increased the expression of il1b gene in PMNs. Blocking and inhibiting IL-1β release effectively counteracted the enhancing effect of GM-CSF on the bactericidal function of PMNs. RmGM-CSF enhances the bactericidal function of PMNs in vivo and improves the prognosis of secondary pneumonia in septic mice, and recombinant GM-CSF increases IL-1β precursor reserves, which, if stimulated, can rapidly enhance the bactericidal capacity of PMNs.
2024-03-01 | GSE227162 | GEO
Project description:Severe congenital neutropenia (SCN) is a rare disorder characterized by a maturation arrest of myeloid progenitor cells in the bone marrow and severe reduction in the amount of circulating neutrophils. Loss-of-function mutations in the CSF3R (the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor) have been reported in a handful of cases. We describe two novel pedigrees with moderate neutropenia. G-CSFR immunostaining was greatly reduced on patient neutrophils. G-CSF did not prolong neutrophil survival or enhanced reactive oxygen species generation, and STAT-3 phosphorylation was absent, while neutrophils did respond to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite a lack of G-CSF signaling, morphology and cellular proteomics were normal. We suggest the major role of G-CSF is not in myeloid differentiation, but in generation of sufficient number of committed progenitor cells for neutrophil release and their survival during inflammation, which corresponds with G-CSFR expression in myeloid cell fractions from bone marrow of healthy individuals.
2020-09-25 | PXD018178 | Pride
Project description:Myeloid-derived suppressor cells (MDSCs) are one of the major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent for the treatment of chemotherapy-induced febrile neutropenia in patients with cancer. However, several reports reveal that G-CSF would play crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited the enhanced proliferation and immunosuppressive activity compared with those differentiated without G-CSF. RNA-seq analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs through the upregulation of gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, the administration of recombinant G-CSF increased MDSCs and attenuated anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, with G-CSF could prevent tumor growth caused by G-CSF, without affecting the promoting myelopoiesis by G-CSF. These results suggest that targeting GGT1 on MDSCs can eliminate the effect of G-CSF in promoting tumor growth. GGsTop could be an attractive combination agent when receiving G-CSF treatment for febrile neutropenia in patients with cancer.
2022-05-13 | GSE183066 | GEO
Project description:Granulocyte colony-stimulating factor (G-CSF) has been utilized to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). SCN patients develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. MDS and AML that arise in these settings are commonly associated with chromosomal deletions. We demonstrate that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell population. Furthermore, primitive hematopoietic progenitors from G-CSF–treated mice show evidence of DNA damage as demonstrated by an increase in double strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein appears to be related to its preferential inhibition of G-CSF–induced proliferation of hematopoietic stem cells. Importantly, genistein does not impair G-CSF–induced proliferation of committed hematopoietic progenitors, nor diminish neutrophil production. The protective effect of genistein was accomplished with plasma levels that are easily attainable through dietary supplementation. aCGH was performed using NimbleGen
2014-02-07 | GSE54737 | GEO
Project description:RATIONALE: G-CSF may prevent or control neutropenia caused by first-line therapy in patients with metastatic colorectal cancer.
PURPOSE: This phase II trial is studying how well G-CSF works in preventing neutropenia during first-line treatment with chemotherapy and bevacizumab in patients with metastatic colorectal cancer.
| 2045094 | ecrin-mdr-crc
Project description:Granulocyte colony-stimulating factor (G-CSF) has been utilized to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). SCN patients develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. MDS and AML that arise in these settings are commonly associated with chromosomal deletions. We demonstrate that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell population. Furthermore, primitive hematopoietic progenitors from G-CSFM-bM-^@M-^Streated mice show evidence of DNA damage as demonstrated by an increase in double strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein appears to be related to its preferential inhibition of G-CSFM-bM-^@M-^Sinduced proliferation of hematopoietic stem cells. Importantly, genistein does not impair G-CSFM-bM-^@M-^Sinduced proliferation of committed hematopoietic progenitors, nor diminish neutrophil production. The protective effect of genistein was accomplished with plasma levels that are easily attainable through dietary supplementation. aCGH was performed using NimbleGen DNA was extracted from bone marrow samples from mice treated with G-CSF or diluent for 4 months and analyzed using NimbleGen 3x720K mouse copy number arrays
2014-02-07 | E-GEOD-54737 | biostudies-arrayexpress
Project description:BackgroundProphylactic factor replacement therapy is recommended over on-demand treatment for preserving long-term joint health in hemophilia. Extended half-life products, including efmoroctocog alfa/eftrenonacog alfa (recombinant factor VIII [FVIII]/FIX Fc fusion proteins; herein rFVIIIFc/rFIXFc), have the potential to reduce treatment burden with less frequent administration and improve bleed prevention.ObjectivesWe report post hoc data from patients with hemophilia A or B (HA/HB) who switched from prestudy on-demand FVIII/FIX to rFVIIIFc/rFIXFc prophylaxis at the start of A-LONG/B-LONG or start of/during ASPIRE/B-YOND phase 3 studies.MethodsPatients with ≥6 months rFVIIIFc/rFIXFc prophylaxis were enrolled. Treatment exposure, dosing, annualized bleeding rates, joint health, and health-related quality of life (HRQoL) outcomes were assessed. Results were also stratified by age.ResultsSixty-seven patients with HA and 50 with HB were analyzed; ≥60% were from regions outside Europe/North America, predominately those aged 12 to 25 years. No subjects returned to on-demand treatment postswitch.After switch to rFVIIIFc/rFIXFc prophylaxis, median annualized bleeding rates were reduced and sustained at low levels with stable factor usage across age groups (median treatment duration: 4.8/3.6 years). HRQoL outcomes improved for all ages; most pronounced changes were in the sports and leisure and physical health domains. After switch to rFVIIIFc prophylaxis, total modified Hemophilia Joint Health Score and joints with pain decreased in 64.6% and 29.2% of patients with HA. Insufficient data from patients with HB limited joint health evaluation of rFIXFc.ConclusionsFindings add to existing evidence and demonstrate the clinical and HRQoL benefits of switching patients from on-demand treatment to rFVIIIFc/rFIXFc prophylaxis.
| S-EPMC10502440 | biostudies-literature
Project description:Optic neuropathy is a major cause of irreversible blindness worldwide, and no effective treatment is currently available. Secondary degeneration is believed to be the major contributor to retinal ganglion cell (RGC) death, the endpoint of optic neuropathy. Partial optic nerve transection (pONT) is an established model of optic neuropathy. Although the mechanisms of primary and secondary degeneration have been delineated in this model, until now how this is influenced by therapy is not well-understood. In this article, we describe a clinically translatable topical, neuroprotective treatment (recombinant human nerve growth factor, rh-NGF) predominantly targeting secondary degeneration in a pONT rat model. Topical application of rh-NGF twice daily for 3 weeks significantly improves RGC survival as shown by reduced RGC apoptosis in vivo and increased RGC population in the inferior retina, which is predominantly affected in this model by secondary degeneration. Topical rh-NGF also promotes greater axonal survival and inhibits astrocyte activity in the optic nerve. Collectively, these results suggest that topical rh-NGF exhibits neuroprotective effects on retinal neurons via influencing secondary degeneration process. As topical rh-NGF is already involved in early clinical trials, this highlights its potential in multiple indications in patients, including those affected by glaucomatous optic neuropathy.
| S-EPMC7042238 | biostudies-literature