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)

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was given to an intensive-care patient with polytrauma in a life-threatening situation with acquired agranulocytosis and sepsis. Mature granulocytes reappeared in the blood 2 days after initiation of rhGM-CSF therapy; granulocyte precursors peaked at 43% after 5 days. Bone marrow examination performed 7 days after the beginning of rhGM-CSF therapy revealed complete regeneration of granulopoiesis. The functional analysis of these blood leukocytes in vitro showed regular production of reactive oxygen radicals. Clinically, the patient recovered without any serious side effects due to the rhGM-CSF therapy. These results suggest that rhGM-CSF accelerates granulocyte recovery from acquired agranulocytosis with the presence of their functional activity.
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PMID:Instant therapy of acquired agranulocytosis and sepsis by recombinant granulocyte-macrophage colony-stimulating factor in a polytrauma patient. 830 35

Despite the increasing use of granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of chemotherapy-induced neutropenia, few studies have focused on the activity and toxicity of the different clinically used dosages of GM-CSF. Forty-four patients with "poor-risk" (advanced disease, according to the Indiana University classification) testicular cancer were treated with a dose-intensified chemotherapy regimen of cisplatin (30 mg/m2), etoposide (200 mg/m2), and ifosfamide (1.6 g/m2), given on days 1-5 for a total of four cycles at planned intervals of 21 days. Patients (pts) received GM-CSF, either 10 (22 pts; 70 cycles evaluable) or 5 micrograms/kg body wt. daily s.c. (22 pts; 72 cycles evaluable), starting the first day after chemotherapy for 10 consecutive days. Overall, 34 patients (78%) achieved a favorable response (CR or PR with negative tumor markers), six patients (14%) failed this chemotherapy regimen, and four patients (9%) died of therapy-related complications. The durations of both neutropenia and thrombocytopenia increased with the number of treatment cycles given. The duration of granulocytopenia after the fourth PEI cycle was significantly shorter for patients receiving 10 micrograms/kg than for those with 5 micrograms/kg per day of GM-CSF (9 vs 13 days; p < 0.05). The median duration of thrombocytopenia < 20,000/microliters after the fourth cycle of PEI was also significantly reduced in favor of patients receiving 10 micrograms/kg of GM-CSF (4 vs 9 days; p < 0.02). However, there were no differences in the frequency of severe infections or in the achieved dose intensity. Five patients (11%) discontinued GM-CSF due to side effects (three anaphylactoid-type reactions, one myalgia and fever, one cutaneous toxicity). No difference in the frequency of side effects was seen between patients receiving 5 and those receiving 10 micrograms/kg per day of GM-CSF. The dose of 5 micrograms/kg per day of GM-CSF may be sufficient to ameliorate neutropenia following standard-dose chemotherapy, while higher dosages of GM-CSF may be advantageous in patients receiving repetitive cycles of dose-intensified chemotherapy.
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PMID:Comparison of 5 vs 10 micrograms/kg per day of GM-CSF following dose-intensified chemotherapy with cisplatin, etoposide, and ifosfamide in patients with advanced testicular cancer. 834 33

Colony-stimulating factors have been shown to have a myeloprotective effect when administered following chemotherapy. Chemotherapy of short duration with predominantly cell-cycle nonspecific agents has been most used. The myeloprotective effects of colony-stimulating factors given after cell-cycle specific or continuous infusion chemotherapy have not previously been assessed. Twenty-one evaluable patients with metastatic breast cancer progressing after one prior chemotherapy regimen were treated with continuous infusion vinblastine 2.0 mg/m2/day for 5 days. After the second chemotherapy cycle, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for 10 days. Serial complete blood counts, differential, and platelet counts were obtained to document myelotoxicity. GM-CSF administration resulted in a significantly shorter duration of granulocytopenia, < 500/microliters, at the maximum GM-CSF dose. Significantly more rapid recovery of granulocytes to > 500/microliters, > 1000/microliters, and > 1500/microliters was seen with all doses and schedules of GM-CSF administered. The nadir absolute granulocyte counts were unaffected. GM-CSF given after continuous infusion cell-cycle specific chemotherapy is therefore myeloprotective.
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PMID:The myeloprotective effect of recombinant human granulocyte-macrophage colony-stimulating factor given sequentially with continuous infusion vinblastine in metastatic breast cancer patients. 845 4

Granulocytopenia is a complication of human immunodeficiency virus disease, as well as a toxic manifestation of zidovudine therapy. To evaluate pharmacokinetic and pharmacodynamic relationships, 11 AIDS-AIDS-related complex patients who had developed zidovudine-associated granulocytopenia (mean absolute neutrophil count, 1,077/mm3) were examined after addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to zidovudine. GM-CSF was administered as a daily (1.0 or 0.3 micrograms/kg) or every-other-day (0.3 micrograms/kg) subcutaneous dose over a 28-day period. Zidovudine was continued at the same daily dosage as was previously being administered. Of 11 patients, 7 (1.0 micrograms/kg, n = 5; 0.3 micrograms/kg, n = 2) had a pharmacologic response to GM-CSF with an increase to a mean absolute neutrophil count of 3,189 cells per mm3 at 4 weeks (P < 0.05). The peak concentration of GM-CSF in plasma ranged from 11.5 to 84.4 pg/ml, and the time to peak ranged from 1 to 3 h. No correlation between GM-CSF disposition and hematologic response was noted. A decreased plasma zidovudine-glucuronide/zidovudine ratio was noted after 1 week of GM-CSF, and an increase in the area under the plasma concentration-versus-time curve for zidovudine was found in three patients after 4 weeks. Low doses of GM-CSF can raise the granulocyte count in patients with zidovudine-induced neutropenia. The use of GM-CSF and zidovudine may represent a viable treatment option for persons with human immunodeficiency virus infection who develop neutropenia while receiving zidovudine but do not tolerate alternative nucleoside analogs. Further studies are needed to assess the complex interaction between these two agents.
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PMID:Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex. 846 Sep 20

To investigate the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on cytotoxic chemotherapy-induced granulocytopenia, we performed an open nonrandomized clinical trial in 46 patients with malignancies receiving cytotoxic chemotherapy regimen. Twenty-six patients who received two cycles of the identical chemotherapy regimen and had granulocytopenia less than 1 x 10(9) cells/l after the first cycle of chemotherapy were eligible for this study. They received 60, 125 or 250 micrograms/m2/day of rhGM-CSF randomly. The nadirs of peripheral granulocytes demonstrated significantly much higher levels in all dosages studied than those of control cycles. The duration of granulocytopenia was shortened with rhGM-CSF support. Such granulocyte recovery appeared in parallel with increasing dosages of GM-CSF, thus, infections with febrile episodes were reduced. Toxicity of rhGM-CSF was generally well tolerated.
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PMID:Effect of granulocyte-macrophage colony-stimulating factor on chemotherapy-induced granulocytopenia in patients with malignancies. 850 46

Vesnarinone, an oral therapeutic agent for cardiac failure, causes agranulocytosis as a side effect. To elucidate the mechanism of occurrence of the agranulocytosis, we examined the effect of vesnarinone on granulopoiesis using an in vitro human long-term bone marrow culture system. Addition of vesnarinone to the culture decreased the total number of hematopoietic cells, mainly composed of mature granulocytes and macrophages, but increased the number of granulocyte-macrophage progenitor cells (CFU-GM) and CD33-CD34+ cells as compared with an untreated control. Differentiation of CFU-GM was induced by removing the agent from the culture medium, indicating that the effect of vesnarinone was reversible. The agent did not directly affect CFU-GM in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, treatment of stromal cells with vesnarinone repressed the production of G, GM, M-CSF, suggesting that the agent may cause a hematopoietic disorder, agranulocytosis, through the impairment of stromal cell function.
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PMID:Possible involvement of bone marrow stromal cells in agranulocytosis caused by vesnarinone treatment. 935 44

T-cell large granular lymphocyte (T-LGL) leukemia is clinically indolent, but is associated with severe neutropenia in approximately 50% of cases. The pathogenesis of the neutropenia is unclear. We report reversal of severe neutropenia associated with T-LGL leukemia in five patients treated with cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 x 10(9)/L, two had agranulocytosis, and four had recurrent infections. Increased populations of LGL were present in blood and marrow, with a T-LGL immunophenotype (CD3(+)CD8(+)CD16(+/-)CD56(+/-)CD57(+)) shown by multiparameter flow cytometry, and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels. Four patients attained normal neutrophil counts with CSA alone; one required addition of low-dose granulocyte-macrophage colony-stimulating factor. Time to attainment of 1.5 x 10(9)/L neutrophils ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted in recurrent neutropenia. Three patients have maintained normal neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil counts-one of metastatic melanoma and one of complications after aortofemoral bypass surgery. Despite resolution of neutropenia, increased populations of T-LGL cells have persisted in all patients during CSA therapy, as shown by morphology and flow cytometry and by the presence of clonal TCR gene rearrangements in four patients' posttreatment blood samples. We conclude that CSA is an effective therapy for neutropenia associated with T-LGL leukemia, and that resolution of neutropenia despite persistence of abnormal cells implies that CSA may inhibit T-LGL secretion of yet unidentified mediators of neutropenia.
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PMID:Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term response to cyclosporine therapy despite persistence of abnormal cells. 955 95

A 45-year-old female suffering from severe chronic schizophrenia of the paranoid type did not respond to typical antipsychotics. Five weeks after starting therapy with clozapine, she developed a clozapine-induced agranulocytosis (CA). Discontinuation of clozapine and treatment with granulocyte colony-stimulating factor (G-CSF) led to normalization of blood neutrophil counts within three weeks. This report suggests enhanced apoptosis of blood neutrophils during the acute phase of CA resulting from enhanced expression of the pro-apoptotic proteins Bax and Bik and from a decrease of the anti-apoptotic BCl-X(L) mRNA. The time course of decline and recovery of neutrophilic cells, as well as the release pattern of endogenous G-CSF, resembles those of chemotherapy-induced neutropenia. The kinetics of CD 34-positive cells mimics that of cytotoxic progenitor cell mobilization, e. g., after cytostatic drug administration. Our findings argue against the hypothesis that clozapine-mediated inhibition of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) release is involved in CA development. Because clozapine-induced cell death mainly affects the neutrophil lineage, the elucidation of the exact mechanism of CA may open new perspectives for the treatment of psychiatric and possibly hematological disorders.
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PMID:Increased apoptosis of neutrophils in a case of clozapine-induced agranulocytosis - a case report. 1264 75

A 52-year-old woman presented to our clinic for investigation of agranulocytosis and mild lymphocytosis. A diagnosis of T-large granular lymphocyte leukemia was made, based on immunophenotyping findings of the peripheral blood lymphocytes (CD3, CD8, CD16, CD57). Flow cytometric analysis of TCR-Vbeta repertoire showed single Vbeta9 expression on peripheral T-cells. Clonality was also demonstrated with PCR analysis which revealed clonal rearrangement of TCRgamma-chain gene. Granulocyte-macrophage colony-stimulating factor (G-CSF) (G-CSF), cyclosporine, methylprednisolone and oral methotrexate failed to correct the neutropenia. Finally, treatment with 2-deoxycoformycin (DCF) was successful and resulted in complete correction of the neutrophil count. Flow cytometric analysis of TCR-Vbeta repertoire proved to be an effective method to assess the therapeutic response to various treatments and to evaluate residual disease.
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PMID:2-deoxycoformycin in the treatment of T-large granular lymphocyte leukemia. 1280 46

The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral etoposide given on days 1-10 followed by rescue with subcutaneous (s.c.) granulocyte-macrophage colony-stimulating factor (GM-CSF) on days 12-19 as second-line chemotherapy in platinum-pretreated patients (pts) with advanced ovarian carcinoma. Cohorts of three to six pts were treated with doses of oral etoposide from 750 mg m(-2) cycle(-1) escalated to 1250 mg m(-2) cycle(-1) over 10 days, every 3 weeks. Subcutaneous GM-CSF, 400 mug once daily, days 12-19, was added if dose-limiting granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70-100%) and a median time elapsed since the last platinum dose of 10 months (range, 1-24 months), 30% of whom showed visceral metastases, were treated at four dose levels (DLs) of oral etoposide on days 1-10 of each cycle as follows: DL 1, 750 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 2, 1000 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 3, 1000 mg m(-2) cycle(-1), with GM-CSF, six pts; and DL 4, 1250 mg m(-2) cycle(-1), with GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative sepsis associated with granulocytopenia grade 4. Two more pts developed uncomplicated granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral etoposide 1000 mg m(-2) cycle(-1), days 1-10, followed by s.c. GM-CSF 400 mug, days 12-19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the therapy with oral etoposide given over 10 days followed by s.c. GM-CSF in platinum-pretreated patients with advanced ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.
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PMID:Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer. 1575 78


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