Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

We administered Escherichia coli-derived recombinant human granulocyte-macrophage colony-stimulating factor to 61 patients with malignancy, 36 of whom had normal peripheral blood counts and 25 of whom had peripheral cytopenia due to underlying bone marrow disease, to compare the efficacy of two different routes of administration to stimulate the in vivo granulopoiesis: i.e., continuous i.v. infusion and s.c. injection. Three well-tolerated dose levels were investigated. Application of granulocyte-macrophage colony-stimulating factor resulted in dose-dependent increases in circulating neutrophils, eosinophils, and monocytes and an increase in bone marrow cellularity, irrespective of route of administration. In some patients, mild side effects, including bone pain, dyspnea, flu-like symptoms, and a decrease of platelet counts, were recorded, but they were less pronounced when the hormone was administered subcutaneously.
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PMID:Stimulation of granulopoiesis in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor: assessment of two routes of administration. 225 59

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was investigated in 29 patients with advanced malignancy in phase Ib trial. Patients were treated at six different dose levels (30-1000 micrograms/m2/day) with either daily intravenous bolus injection or 24 hours continuous infusion for 5 days or 2 weeks. Administration of rh GM-CSF resulted in a broad spectrum of dose-, route-, and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total white blood cell (WBC) count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets and reticulocytes was not induced. Within one week after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnoea and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules employed and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase turnover and function of leukocytes in vivo may prevent neutropenia and infections, when GM-CSF is adjunctively added to cytotoxic cancer therapy.
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PMID:Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: a phase ib clinical study. 246 45

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) was investigated in 30 patients with advanced malignancy in a phase Ib trial. Patients were treated at four different dose levels (120 to 1,000 micrograms/m2/d) by either daily intravenous (IV) bolus injection or 24-hour continuous infusion. Administration of rh GM-CSF resulted in a broad spectrum of dose- and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total WBC count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets, and reticulocytes was not induced. Within five days after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always rapidly reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnea, and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules used and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase number and function of leukocytes in vivo may prevent neutropenia and infections when GM-CSF is added to cytotoxic cancer therapy.
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PMID:Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor. 264 95

Twenty patients with progressive metastatic solid tumours were entered into a study to evaluate the biological effects and toxicity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was given as half-hour intravenous infusions during two 10-day phases of daily treatments (separated by 10 days without GM-CSF) and over a final phase of 20 days of alternate day infusions. Doses were escalated in steps from 0.3 to 60 micrograms kg-1 day-1 between successive patient groups. Significant increases (P less than 0.005) of total leucocyte, neutrophil and eosinophil polymorph counts were seen over the periods of daily infusions (up to four-fold rises of total white count) at dose levels of 10 micrograms kg-1 and above. Counts produced at 30 micrograms kg-1 were significantly higher than at 10 micrograms kg-1 (P less than 0.025). Toxic side effects of GM-CSF included mild transient pyrexias, bone pain and pruritus. The maximum tolerated dose was 60 micrograms kg-1, which produced severe toxicity in 80% of patients. The toxicity at this dose included pericarditis and dyspnoea ascribed to a 'capillary-leak' syndrome. One patient receiving 60 micrograms kg-1 died as a result of a pulmonary embolus. Seven patients with previously rapidly progressive metastatic tumours experienced stabilisation of disease while receiving GM-CSF and one patient with a previously heavily pretreated metastatic soft tissue sarcoma underwent a greater than 50% reduction of tumour volume. Patients undergoing chemotherapy may benefit both from a reduction of the myelosuppressive effects of cytotoxic agents and from an antitumour effect if GM-CSF is incorporated into future regimens.
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PMID:Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions--a phase I dose-toxicity study. 266 7

Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of the clinical effects after the first dose of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor. 268 97

Recombinant yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 10 patients after autologous bone marrow transplantation for Hodgkin's disease given as a 24-h continuous intravenous infusion from the day of marrow infusion until the patient had obtained an absolute neutrophil count of 1.5 x 10(9)/L for 2 consecutive days or until day 30, whichever occurred first. Results were compared with results from 18 historical control patients who did not receive GM-CSF but were otherwise treated in a similar fashion. The infusion of GM-CSF led to a significantly faster neutrophil and monocyte recovery compared to the patients in the historical control group. The median days to achieve an absolute neutrophil count for the GM-CSF group and the control group were 0.5 x 10(9)/L; 9.5 and 14 days; 1.0 x 10(9)/L: 10 and 18 days; 1.5 x 10(9)/L: 11 and 29 days. No significant difference was found with respect to platelet engraftment and red cell transfusion requirements. GM-CSF therapy was discontinued at a median of 12 days. Hospitalization was also shorter for the GM-CSF group (22.5 vs. 26.5 days) and no patient in the GM-CSF group had to be readmitted after initial discharge. The incidence of documented infections was similar among both patient groups and no difference was noted in terms of antimicrobial usage. Some side effects occurred with the continuous infusion of GM-CSF, particularly fluid retention, dyspnea, fever, diarrhea, and bone pain leading to early discontinuation of GM-CSF in 2 patients. The data suggest that a continuous 24-h infusion of GM-CSF significantly accelerates myeloid engraftment, leading to earlier discharge from the hospital.
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PMID:Granulocyte-macrophage colony-stimulating factor after autologous marrow transplantation for Hodgkin's disease. 770 29

Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM-CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.
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PMID:Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers. 838 25

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) can be expressed in yeast, bacteria, or mammalian cells. Expression in each system results in a protein that differs, to a varying extent, from native GM-CSF. Like the native protein, yeast-expressed GM-CSF is glycosylated and has 127 amino acids, but differs from native GM-CSF in molecular mass and in the substitution of leucine for proline at position 23. GM-CSF expressed in Escherichia coli bacteria is not glycosylated, has six fewer amino acids than the native protein, and an extra methionine at position 1. A review of laboratory studies shows that these differences in physiochemical properties result in variations in the pharmacokinetics, biologic activity, and immunogenicity of GM-CSF expressed in different host cells. These variations may lead to an increased clinical toxicity with GM-CSF expressed in E coli versus that produced in yeast. A total of 32 clinical trials were reviewed to determine the relative frequency of adverse events in patients treated with GM-CSF expressed in E coli versus that expressed in yeast. In general, the median reported frequency of adverse events was higher in patients treated with E coli-derived GM-CSF. The median frequencies of fluid retention, dyspnea, fever, myalgias/bone pain/joint pain, and rash were 8.3%, 13.4%, 21.7%, 16%, and 14.3%, respectively, in patients receiving GM-CSF expressed in yeast, versus 18.4%, 55.2%, 40.7%, 28.5%, and 12.5%, respectively, in patients treated with GM-CSF expressed in E coli. Thus data in the literature support the view that the GM-CSF expression system influences the pharmacokinetic properties, biologic activity, and clinical toxicity of GM-CSF.
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PMID:Clinical properties of yeast-derived versus Escherichia coli-derived granulocyte-macrophage colony-stimulating factor. 845 48

The potential antitumoral effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) led us to evaluate GM-CSF alone or with dacarbazine (DTIC) in metastatic melanoma in first line randomized phase II. Treatment was arm A: GM-CSF: 5 microg kg(-1), bid, 14 consecutive days every 21 days and arm B: GM-CSF: 5 microg kg(-1), bid, day 2 to day 19 every 21 days and DTIC: 800 mg m(-2), day 1 of each cycle. 32 patients (pts) were included, 15 pts in arm A and 17 in arm B. All pts had visceral metastatic sites. 9 had only one metastatic site. The median number of cycles given was 2 in arm A and 3 in arm B. 100% and 89.4% of the planned dose of GM-CSF was given in arm A and arm B respectively. No objective response was obtained. 19 pts experienced at least WHO grade 3 toxicity. All pts had fever, 29 had a decrease in performance status and 23 had pain. Grade 3 toxicity were fever (38.7%), decrease in performance status (32.3%), pain (19.4%) and dyspnoea (12.5%). In this study, GM-CSF alone or in association with DTIC did not induce any antitumoral activity with subsequent toxicity.
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PMID:Granulocyte-macrophage colony-stimulating factor alone or with dacarbazine in metastatic melanoma: a randomized phase II trial. 1172 Apr 30

The current mainstay of treatment for pulmonary alveolar proteinosis (PAP) is whole-lung lavage. Therapy with granulocyte-macrophage colony-stimulating factor is a possibility, although its long-term safety has not been determined. An alternative procedure is selected lobar lavage by fiberoptic bronchoscopy (FOB). We report here our experiences with lobar lavage by FOB in treating three patients with PAP. PAP was diagnosed in three patients (two men, one woman) who had dyspnea and hypoxemia after undergoing open-lung biopsy. The patients underwent lobar lavage by FOB under local anesthesia. The bronchoscope was wedged into a lobar bronchus. Approximately 2,000 mL warm normal saline solution was instilled via syringe in 50-mL aliquots through a fiberoptic bronchoscope. After undergoing multiple lobar lavages, two patients showed clinical, physiologic, and radiologic improvement. The third patient, who had more advanced disease, showed improvement only in oxygenation. The major complications were severe cough and hypoxemia during lavage. Our experience suggests that bronchoscopic lobar lavage is simple and safe, and may find application in patients in whom a whole-lung lavage with generalized anesthesia may be hazardous, and in patients with less advanced disease whose proteinaceous substances can be removed with a small volume of lavage fluid.
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PMID:Pulmonary alveolar proteinosis: treatment by bronchofiberscopic lobar lavage. 1237 31


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