Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural suppressor (NS) cells, which are Thy-1-, immunoglobulin-, and nonadherent cells with relatively low density (1.063 to 1.075 g/ml), inhibit not only the proliferation of spleen cells which have been stimulated by allogeneic cells or mitogens but also the proliferation of tumor cell lines. Cell-to-cell contact is not necessary for NS cells to exert NS activity. Being radioresistant, DNA synthesis is not necessary for NS cells to suppress proliferation. However, protein synthesis is necessary, since puromycin blocks NS cell activity. In addition, NS cells were found to secrete a factor which inhibits DNA synthesis. Of the various cytokines tested, interleukin 3 and granulocyte-macrophage colony-stimulating factor enhance NS activity. These results suggest that NS cells play an important role in the suppression of not only immune responses but also tumor growth.
Cancer Res 1990 May 01
PMID:Inhibition of tumor cell proliferation by natural suppressor cells present in murine bone marrow. 213 55

30 patients with chemotherapy-related leukopenia (white cells 1.0 x 10(9)/l or lower) and fever (temperature 38.5 degrees C or higher) were treated in a double-blind randomised trial with standard antibiotics and 7 days of intravenously administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 2.8 micrograms/kg per day) or placebo. GM-CSF administration resulted in a faster percentage increase of peripheral neutrophil count after 2 and 3 days of treatment, except in patients treated with ablative chemotherapy and autologous bone-marrow transplantation. However, GM-CSF did not shorten the period of fever or antibiotic administration. No side-effects were observed; in particular tumour necrosis factor alpha and interleukin-6 did not increase in the 5 GM-CSF patients tested. These data suggest that a subgroup of patients with chemotherapy-related leukopenia and fever may benefit from GM-CSF treatment in view of the observed effects on neutrophil count.
Eur J Cancer 1990
PMID:Efficacy and tolerability of recombinant human granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related leukopenia and fever. 214 17

We studied the effects human recombinant granulocyte-macrophage colony-stimulating factor and human recombinant interleukin-3 on the colony formation of three human solid tumor cell lines. Using a modified double-layer soft agar clonogenic assay rhGM-CSF enhanced colony formation of all cell lines tested in a dose dependent manner (up to twofold for the breast cancer cell line BT-20, up to 163% of the control for the hypernephroma cell line C 94 and up to 147% for the non-small cell lung cancer cell line CCL 185 at a concentration of 100 ng/ml). RhIL-3 stimulated colony formation of the cell lines C 94 and BT-20, whereas on the cell line CCL 185 rhIL-3 had no effect even at the highest dose level tested (100 ng/ml). Combinations of growth factors showed subadditive stimulation on two cell lines tested (BT-20, C 94). These data indicate that haematopoietic growth factors exert a growth promoting activity on certain solid tumor cells in vitro at physiological concentrations. Therefore our results suggest that the application of these factors in immuno- and myelosuppressed cancer patients after high dose chemotherapy should be seen in light of a possible co-stimulation of the malignant cells.
Cancer Lett 1990 Apr 30
PMID:Stimulation of colony formation of various human carcinoma cell lines by rhGM-CSF and rhIL-3. 215 47

The expression of a nonspecific cross-reacting antigen (NCA) species on the cell surface of the human promyelocytic leukemia cell line HL-60 was investigated via binding of 125I-labeled carcinoembryonic antigen (CEA) and NCA-specific monoclonal antibodies (Mabs). Very low specific binding of the CEA-specific Mab35 was found, whereas the CEA- and NCA-recognizing Mab47 showed 20-fold higher binding. The number of binding sites for Mab47 on HL-60 cells is lower than on normal granulocytes and is modulated by inducers of cellular differentiation and growth. Dimethylsulfoxide (DMSO), an inducer of neutrophilic differentiation, increased Mab47 binding in a time-dependent manner up to 4-fold after 7 days. In contrast, phorbol-12-myristate-13-acetate which induces differentiation into monocyte/macrophages led to a loss of binding sites. Mab47 binding was also decreased by granulocyte-macrophage colony-stimulating factor and this effect was enhanced in the presence of DMSO during the first 3 days of DMSO treatment. It is concluded that agents affecting neutrophilic differentiation or cell growth act in an opposite manner on NCA expression of HL-60 cells. NCA expression is not crucial for neutrophilic differentiation because it can be suppressed by granulocyte-macrophage colony-stimulating factor early in the differentiation program without affecting cell maturation.
Cancer Res 1990 Dec 01
PMID:Regulation of the cell surface expression of a nonspecific cross-reacting antigen variant during differentiation of HL-60 cells. 217 25

Two series of five consecutive patients with small cell lung cancer were treated with an "accelerated" chemotherapy regimen of cyclophosphamide-doxorubicin-vincristine (CAV) and cisplatin-etoposide (PE) alternated possibly every week. In the first group of patients (median age 49 years, range 46-52) recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) was given as soon as grade IV leukopenia occurred, while in the second group (median age 59 years, 55-68) no growth factor was administered. The mean interval between chemotherapy courses and the mean duration of chemotherapy were 10 and 57 days, respectively, in the patients supported with GM-CSF compared with 13 and 72 days in the control group. One GM-CSF treated patient was withdrawn after the third cycle because of severe toxicity. The mean white blood cell and platelet nadirs were 600 and 46,000/microliters in the first group vs. 840 and 105,000/microliters in the controls. Overall chemotherapy dose-intensity was increased by two fold in the patients given GM-CSF compared with a 1.5 fold increase in the control patients. In all cases, irrespective of their treatment, there was an impaired colony forming capacity of circulating and marrow haemopoietic progenitor cells when grade IV leukopenia occurred, with recovery after the end of leukopenia. This pilot study suggests that accelerated CAV/PE chemotherapy is feasible both with and without GM-CSF. Different GM-CSF schedules as well as combinations of different haemopoietic growth factors may further improve dose-intensity.
Eur J Cancer 1990
PMID:Accelerated chemotherapy with or without GM-CSF for small cell lung cancer: a non-randomised pilot study. 217 14

Colony-stimulating factors (CSFs) have important effects on mature myeloid cells in addition to their regulatory role in haemopoiesis. Exposure of neutrophils to granulocyte macrophage-CSF (GM-CSF) increases chemotaxis, phagocytosis and cytotoxicity and primes the cells for enhanced oxidative metabolism in response to stimuli, such as formylated oligopeptides derived from bacteria (f-Met-Leu-Phe) and endogenous activated complement components (C5a). GM-CSF induces time-dependent changes in neutrophil f-Met-Leu-Phe receptor number and affinity that correspond to changes in functional activity. The neutrophil IgA Fc receptor is also modulated by GM-CSF such that it develops a high affinity state and transduces a phagocytic signal. The ability to regulate the number and activity of mature myeloid effector cells in vivo establishes unique therapeutic opportunities in the area of infectious disease, cancer treatment, bone marrow transplantation and augmentation of host defence in immunodeficient patients.
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PMID:Responses of neutrophils to myeloid growth factors. 218 Jun 50

Thirty-two assessable patients with metastatic urothelial tumors refractory to standard chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were treated with escalated doses of MVAC plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Results of this phase I trial revealed that escalated MVAC (30 mg of methotrexate/m2, 4 mg of vinblastine/m2, 60 mg of doxorubicin/m2, and 100 mg of cisplatin/m2) can be tolerated by heavily pretreated patients. The side effects of rhGM-CSF are dose- and schedule-dependent. The maximum tolerated dose is 250 micrograms/m2 per day as a single dose administered subcutaneously (SC) for 10 consecutive days. This dose is well tolerated in outpatients, resulting in only modest fever and few side effects. The same dose delivered as a continuous infusion or a higher dose delivered either as a continuous infusion or SC caused significant side effects. For phase II trials, the starting dose of rhGM-CSF when combined with escalated MVAC is 120 micrograms/m2 per day SC for 10 consecutive days. forty percent of the treated patients responded, seven (23%) with complete remission and five (17%) with partial remission. This response rate is higher than anticipated from such a modest dosage escalation in chemotherapy-refractory patients.
J Natl Cancer Inst 1990 Apr 18
PMID:Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor. 218 Nov 51

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 10 patients with refractory malignancies, 2 patients who had myelodysplastic syndromes with severe neutropenia and to a patient who had delayed marrow recovery after 3 cycles of therapy for acute leukemia. A marked neutropenia and monocytopenia was observed within 5 min after an i.v. injection of GM-CSF. This persisted for 1-2 h and seemed related to activation of an adhesive glycoprotein (MO1) on the surface of these cells. With continued daily i.v. administration of GM-CSF, all patients with refractory malignancies developed a striking leukocytosis. Total leukocyte counts reached 75,000/microliters within 2 weeks of treatment. This was due to an increase in band and segmented neutrophils, eosinophils and monocytes. Accelerated myelopoiesis required the continuous presence of GM-CSF; with pump failure for 24 h or discontinuation after 14 days, leukocyte counts returned to normal levels in 24-48 h. GM-CSF also increased myelopoiesis in the patients with myelodysplastic syndromes or following anti-leukemic treatment. These observations suggest that this growth factor should prove a useful adjunct in the treatment of patients with malignancies and bone marrow failure.
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PMID:Use of granulocyte-macrophage colony-stimulating factor in patients with malignancy and bone marrow failure. 218 42

It has long been known that complex interactions occur between tumors and normal host immune cells. The human melanoma cell line A375 has been used previously as an indicator cell for tumor cell cytotoxicity mediated by monocytes. During other studies on this tumor cell line, we noted that the conditioned media harvested from A375 cultures induced both the human monocytoid cell line U937 and human blood monocytes to release the cytokine tumor necrosis factor (TNF). We characterized this tumor factor which induced TNF release by monocytic cells. Purification was performed using ammonium sulfate precipitation, ion exchange (DEAE) chromatography, gel filtration, and reversed-phase high performance liquid chromatography. The factor copurified with granulocyte-macrophage colony-stimulating factor (GM-CSF). The purified material caused the release of TNF by U937 cells and stimulated formation of granulocyte-macrophage colonies in methyl cellulose. TNF release by U937 cells in response to A375-conditioned medium was inhibited by neutralizing antibodies to GM-CSF. The TNF-inducing activity in A375-conditioned medium was completely removed by an anti-GM-CSF affinity column. Western blotting using antibodies to GM-CSF confirmed a single Mr27,000 band in A375-conditioned medium. We found that recombinant human GM-CSF stimulated TNF production by the same cells as the tumor-conditioned medium. These data show that A375 human melanoma cells produce GM-CSF, which in turn causes TNF production by cells in the monocyte lineage. The combination of GM-CSF production by the tumor and TNF production by immune cells may influence not only tumor growth but also some of the paraneoplastic syndromes associated with malignancy such as hypercalcemia, cachexia and leukocytosis.
Cancer Res 1990 May 01
PMID:Stimulation of tumor necrosis factor release from monocytic cells by the A375 human melanoma via granulocyte-macrophage colony-stimulating factor. 218 30

Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara-C (AC) (NOAC) was active in refractory non-Hodgkin's lymphoma (NHL) but myelosuppression was dose-limiting. In a pilot study, we investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM-CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were greater than 3.0/nl for 3 consecutive days. Twenty-three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM-CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM-CSF (P = 0.0058), and that of thrombocytopenia (less than 20.0/nl), 3 days versus 7 days (P greater than 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM-CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM-CSF. The following side effects were associated with the administration of rhGM-CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM-CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM-CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM-CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response.
Cancer 1990 Aug 01
PMID:Mitoxantrone/high-dose Ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study. 219 41


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