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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A dose-finding study was performed in 27 ovarian cancer patients to define the maximum tolerated dose of a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with a fixed dose of carboplatin. The median age of the patients was 55 years (age range, 30 to 74 years), the median performance status was 0 (range, 0 to 2), and the sizes of tumors residual to first surgery were identified as > or = 1 cm (14 patients) or less than 1 cm (13 patients). All patients received carboplatin at a fixed dose of 300 mg/m2 over 1 hour. Paclitaxel was administered as a 3-hour infusion at five dose levels, starting at 150 mg/m2 and increasing in 25 mg/m2 increments to 250 mg/m2. In the absence of toxicity, courses were repeated every 4 weeks for a total of six cycles. Mild emesis, general alopecia, and moderate myalgias occurred. Hypersensitivity and cardiotoxicity were observed in 7.4% and 14.8% of patients, respectively. Moderate peripheral neuropathy was experienced by 30% of patients. Grade 3 and 4 neutropenia lasted less than 7 days; no patients required hospitalization for sepsis or febrile neutropenia, and no supportive treatment with granulocyte/granulocyte-macrophage colony-stimulating factor was needed. Twenty-one patients were evaluable for response. Overall response rate (complete response+partial response) was 81%, and responses were observed at all paclitaxel dose levels. The maximum tolerated dose was not achieved. In conclusion, with a fixed dose (300 mg/m2) of carboplatin, paclitaxel can be administered by 3-hour infusion at 250 mg/m2 with manageable toxicity and no supportive care is needed.
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PMID:Pilot study with fixed-dose carboplatin and escalating paclitaxel in advanced ovarian cancer. 855 81

While the overall incidence of infection has remained constant at approximately 7/1000 livebirths, the last decade has witnessed a reduction in early onset infections and a relative increase in nosocomial sepsis, chiefly with coagulase-negative staphylococci. Immaturity of host defence mechanisms contributes to an increasing susceptibility to infection with decreasing gestational age and birth weight. In the past, efforts to enhance host defence have included the use of granulocyte infusions, fresh frozen plasma, exchange blood transfusions and immunoglobulin therapy. Current trials are investigating the use of agents which enhance endogenous defence mechanisms, such as, recombinant human granulocyte colony-stimulating factant and recombinant human granulocyte-macrophage colony-stimulating factor and of pentoxifylline. In the meantime strict attention to handwashing and aseptic technique remain the best methods of preventing nosocomial sepsis.
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PMID:New modalities for treating neonatal infection. 883 42

A dose-finding study involving 27 untreated patients with ovarian cancer was performed to define the maximum tolerated dose of a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with a fixed dose of carboplatin. The median age of the study patients was 55 years (age range, 30 to 74 years), the median Eastern Cooperative Oncology Group performance status was 0 (range, 0 to 2), and residual tumor to first surgery was > or = 1 cm in 14 patients and less than 1 cm in 13 patients. All patients received carboplatin at a fixed dose of 300 mg/m2 over 1 hour. Paclitaxel was administered at five dose levels starting at 150 mg/m2 and increasing in 25-mg/m2 increments to 250 mg/m2. In the absence of toxicity, courses were repeated every 4 weeks for a total of six cycles. World Health Organization grade 1 hypersensitivity and cardiotoxicity were observed in 7.4% and 14.8% of patients, respectively. Moderate peripheral neuropathy was experienced by 29.6% of patients. Grades 3 and 4 neutropenia lasted less than 7 days; no patient required hospitalization for sepsis or febrile neutropenia, and no supportive treatment with granulocyte or granulocyte-macrophage colony-stimulating factor was needed. The maximum tolerated paclitaxel dose was not achieved.
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PMID:A phase I trial with fixed-dose carboplatin and escalating doses of paclitaxel in advanced ovarian cancer. 904 31

The influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma on the restoration of impaired TNF-alpha release in LPS-desensitized mice or their refractory macrophages was investigated. Mice pretreated with GM-CSF or IFN-gamma (50 microg/kg i.v.) and injected with 3 mg/kg LPS i.p. displayed increased plasma TNF-alpha levels compared with LPS controls. IL-10 was marginally up-regulated by GM-CSF but abrogated by IFN-gamma pretreatment. LPS-tolerant mice (30 microg/kg LPS i.p., -24 h) showed an attenuated plasma TNF-alpha and IL-10 response to LPS and survived LPS shock. Pretreatment of such mice with GM-CSF or IFN-gamma restored the previously impaired TNF-alpha response. In cultures of murine monocyte/macrophage-containing cell populations, i.e., alveolar, peritoneal, spleen, bone marrow cells, or blood, the presence of GM-CSF or IFN-gamma (10 ng/ml) resulted in an enhanced release of TNF-alpha initiated by 1 microg/ml LPS. Cells from LPS-tolerant mice showed a diminished responsiveness to LPS. However, when exposed to GM-CSF or IFN-gamma ex vivo, their TNF-alpha response to LPS was partially restored. These findings characterize GM-CSF and IFN-gamma as potent enhancers of LPS-induced TNF-alpha production in normal as well as in experimentally immunocompromised mice and provide the rationale for further experiments to explore the pharmacologic use of these cytokines for restoration of immunocompetence in sepsis-associated immunosuppression.
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PMID:Granulocyte-macrophage colony-stimulating factor and IFN-gamma restore the systemic TNF-alpha response to endotoxin in lipopolysaccharide-desensitized mice. 905 23

Neutrophils play a key role in the pathophysiology of septic multiple organ dysfunction syndrome (MODS) through excessive release of toxic granule components and reactive oxygen metabolites with consequent tissue destruction. The increase of senescent neutrophils during sepsis indicates a potential breakdown of autoregulatory mechanisms including apoptotic processes to remove activated neutrophils from inflammatory sites. Therefore, neutrophil apoptosis of patients with severe sepsis and its regulatory mechanisms were investigated. Spontaneous neutrophil apoptosis from patients with severe sepsis was significantly reduced in comparison to healthy individuals. Cytokines detected in the circulation during sepsis (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) inhibited neutrophil apoptosis in both groups, though the effect was more distinct in neutrophils from healthy humans. Addition of lipopolysaccharide (LPS) to neutrophils from healthy humans markedly (P < .05) reduced apoptosis which was partially restored through addition of anti-TNF-antibody. Interleukin-10 (IL-10) counteracted (P < .05) inhibition of neutrophil apoptosis induced by LPS, recombinant human (rh) TNF-alpha, rhIFN-gamma, rhG-CSF, and rhGM-CSF, whereas rhIL-4 or rhIL-13 were ineffective. Reduced neutrophil apoptosis during sepsis was concomitant with increased tyrosine phosphorylation, while IL-10 markedly inhibited tyrosine phosphorylation in LPS-stimulated neutrophils. These results identify proinflammatory cytokines and IL-10 as strong regulators of spontaneous neutrophil apoptosis during sepsis. Inhibition as well as acceleration of neutrophil apoptosis seems to be associated with alterations of signal transduction pathways.
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PMID:Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. 934 17

Recombinant GM-CSF has been recently shown to prolong survival of elderly patients with acute myeloid leukemia (AML) by reducing the rate of induction therapy-related mortality. In a prospective, randomized, placebo-controlled, double-blind, multicenter study conducted by the Eastern Cooperative Oncology Group in the United States, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given only to those patients who had hypocellular or remission marrow on day 10 of one or two cycles of standard induction therapy. Although the administration of GM-CSF significantly reduced a wide range of adverse events, the main benefit of this cytokine seems to be mediated by a reduction in sepsis. A similarly designed study, conducted by the Southwest Oncology Group in a directly comparable AML patient population with use of granulocyte colony-stimulating factor (G-CSF) as the supportive cytokine, showed no survival benefit and no reduction in the rates of serious or lethal sepsis. In most current clinical situations, GM-CSF and G-CSF are indistinguishable both in terms of efficacy and toxicity. GM-CSF and G-CSF have very different impacts on the survival of patients with AML. The stimulation of monocyte-macrophage function and proliferation by GM-CSF may mediate the selective benefit of GM-CSF in patients with AML and stem cell transplants. GM-CSF merits further study as therapy for and/or protection against opportunistic sepsis in patients with cancer and will be included in a number of International Oncology Study Group protocols.
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PMID:Monocyte-macrophages, granulocyte-macrophage colony-stimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants. 963 47

In the sequelae of massive traumatic stress, substantial impairment of immunologic reactivity has been demonstrated to correlate clinically with increased susceptibility to serious infection. Posttraumatic immune abnormalities consist basically of two coexistent mechanisms: Hyperinflammation and depression of cell-mediated immune responses. It is our understanding that the endogenous ability of the organism to survive overwhelming trauma is insufficient and requires exogenous support to prevent the conversion from systemic inflammatory response syndrome to bacterial sepsis and septic shock. The objectives of immunomodulatory interventions, which should be started as early as possible after tissue destruction, include a) prevention of excessive macrophage stimulation via neutralization of circulating endotoxins and exotoxins with high doses of polyvalent immunoglobulin and soluble complement receptors, b) global short-term (<72 hrs) down-regulation of inflammatory monocyte/macrophage and polymorphonuclear neutrophil activity, and c) restoration of cell-mediated immune performance to overcome posttraumatic functional paralysis. Among recent promising strategies, the use of granulocyte-macrophage colony-stimulating factor, pentoxifylline, and recombinant human interleukin-13 has been suggested, all of them predominantly down-regulating the Mphi (monocyte/macrophage) inflammatory potential. Cyclooxygenase inhibitors such as indomethacin and thymomimetic peptides can help normalize the immunoreactivity by restoring the forward-regulatory pathway of cell-mediated immunity responses. The efficacy of interferon to reduce infection and deaths in severely injured patients has been assessed in clinical trials. Still other compounds, i.e., CNI-1493, interleukin-11, tissue factor pathway inhibitors, and PGG-Glucan represent auspicious immunomodulatory approaches for control of posttraumatic or postoperative infections.
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PMID:Therapeutic immunomodulatory approaches for the control of systemic inflammatory response syndrome and the prevention of sepsis. 965 18

The immaturity of neonatal phagocytic immunity contributes to increased mortality during neonatal sepsis. Neonates have both quantitative and qualitative neutrophil defects with decreased bone marrow neutrophil storage pool (NSP) reserves, an inability to increase neutrophil production, and defective neutrophil functional activity. Neonates respond to overwhelming sepsis with depletion of the NSP and the development of peripheral neutropenia. The myelopoietic cytokines granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been documented to induce neutrophilia in neonatal animals and human infants, increase the NSP, and upregulate neutrophils for improved functional activity. Preclinical studies in neonatal rats demonstrate increased survival with prophylactic G-CSF during experimental group B streptococcal sepsis. In pilot phase I/II human trials, G-CSF and GM-CSF were demonstrated to be both safe and well tolerated and to induce significant increases in absolute neutrophil count and NSP. Prophylactic GM-CSF in the very low birth weight neonate may reduce the incidence of nosocomial infections. Phase III trials are needed to further delineate the clinical usefulness of these myelopoietic cytokines in neonates with a high predisposition to sepsis.
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PMID:Potential use of granulocyte colon-stimulating factor and granulocyte-macrophage colony-stimulating factor in neonates. 966 63

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance the antimicrobial functions of mature neutrophils. G-CSF differs from GM-CSF in its specificity of action on developing and mature neutrophils, its effects on neutrophil kinetics, and its toxicity profile. The toxicity profile of recombinant (r) GM-CSF is consistent with priming of macrophages for increased formation and release of inflammatory cytokines, whereas rG-CSF induces production of antiinflammatory factors, such as interleukin-1 receptor antagonist and soluble tumor necrosis factor receptors, and is protective against endotoxin- and sepsis-induced organ injury. The low toxicity of rG-CSF, results of animal models of infection, and extensive experience with neutropenic subjects have promoted clinical studies in nonneutropenic subjects, which indicate that rG-CSF may be beneficial as adjunctive therapy for treatment of serious bacterial and opportunistic fungal infections in nonneutropenic patients, including those with alterations in neutrophil function.
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PMID:Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients. 1008 6

The problems of immunologic adaptation during the transitional period from intra- to extrauterine life are responsible for the physiologic immaturity of the immune function in newborn infants. In preterm neonates the immunodeficiency is more severe and prolonged and is associated with a higher incidence of infections and sepsis. Furthermore, due to immaturity of the hematologic system, anemia, thrombocytopenia, and neutropenia are frequently observed in very low birth weight infants. The dysregulation of cytokine and hematopoietic growth factor synthesis is an important contributory factor to the complex deficiency of immunologic and hematologic function in the neonate and may explain the reduced incidence of acute graft-versus-host disease observed after cord blood transplantation in children. Human milk is a rich source of most of the cytokines that are reduced in the neonate. Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin are currently under evaluation in newborn infants with septic neutropenia or anemia of prematurity.
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PMID:Hematopoietic growth factor levels in term and preterm infants. 1022 41


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