Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) causes a transient leucopenia. Radionuclide labelling studies showed this to be due to margination of neutrophils and monocytes predominantly in the pulmonary vasculature. No evidence of complement activation was found. A rapid in-vivo rise in neutrophil cellular adhesion molecule (CAM) expression was observed paralleling the development of the neutropenia. Neutrophils exposed to rhGM-CSF in-vitro showed similar rapid increases in CAM expression. The adherence of chromium-labelled neutrophils to endothelial cell cultures was modestly but highly significantly increased by rhGM-CSF, an effect that was reduced by the binding of a monoclonal antibody to the beta chain of neutrophil CAM. The margination of phagocytic cells induced by rhGM-CSF administration is therefore likely to be due at least in part to increased expression of adhesion promoting glycoproteins. The demargination, however, occurred at a time when neutrophil CAM expression was still high, suggesting that dissociation of the neutrophil-endothelial cell interaction depends on factors other than downregulation of CAM expression. In-vivo modulation of phagocyte CAMS and adhesive properties by GM-CSF may be of importance in the normal inflammatory response.
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PMID:Granulocyte macrophage colony stimulating factor induced changes in cellular adhesion molecule expression and adhesion to endothelium: in-vitro and in-vivo studies in man. 264 37

Granulocyte-macrophage progenitors (CFU-GM) from four patients with childhood onset cyclic neutropenia demonstrated abnormal in vitro proliferative responses to purified, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) when examined in detailed dose-response studies. Marrow aspirate specimens were obtained for these studies from cyclic neutropenia patients (both during neutropenic nadirs and during recovery phases of cycles), from leukemia patients in remission who had received myelosuppressive chemotherapy, and from healthy normal volunteers. Nucleated marrow cells were then isolated by density-gradient centrifugation and cryopreserved to permit studies of CFU-GM from patients and controls to be carried out at the same time and in replicate. Maximum clonal growth of CFU-GM from normal subjects and from individuals recovering from drug-induced myelosuppression was elicited by 20-100 pmol/liter rhGM-CSF, and the CSF concentrations that induced half-maximal responses (ED50) were between 1.0 and 3.0 pmol/liter. In contrast, maximum growth of CFU-GM from the cyclic neutropenia patients required greater than or equal to 1.0 nmol/liter rhGM-CSF and ED50's were greater than 30.0 pmol/liter. These abnormalities in the GM-CSF responsive growth of myeloid progenitors were independent of cycle time and were most apparent with the predominantly neutrophilic 7-d CFU-GM. Moreover, differences in the growth of 14-d CFU-GM could be attributed mostly if not entirely to differences in the generation of neutrophilic colonies. These findings indicate that childhood onset cyclic neutropenia is associated with an underlying disturbance in the GM-CSF responsive growth of myeloid progenitors committed to neutrophilic differentiation.
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PMID:Abnormal responses of myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor in human cyclic neutropenia. 264 15

The toxicity, pharmacokinetics, and hematologic effects of granulocyte-macrophage colony-stimulating (GM-CSF) were studied in a phase I/II trial of 16 patients with myelodysplastic syndrome (MDS). The GM-CSF was administered subcutaneously (SC) daily so as to achieve prolonged blood levels and to establish an outpatient treatment regimen. Four dose levels were administered for ten days: 0.3 microgram/kg/d (three patients), 1.0 microgram/kg/d (three), 3.0 micrograms/kg/d (four), and 10.0 micrograms/kg/d (six). The most common toxicities were fever and a flu-like syndrome, which were dose-dependent. The maximum-tolerated dose was 10.0 micrograms/kg/d, which induced severe rigors (two patients), fever greater than 40 degrees C (one), severe bronchospasm (one), and WBC 60,000 (one). In one patient, refractory anemia with excess blasts in transformation (RAEB-T) progressed to acute nonlymphocytic leukemia after two doses of GM-CSF, and the patient died of leukemia that did not respond to chemotherapy. After doses of 3.0 and 10.0 micrograms/kg, serum GM-CSF levels peaked at 3.8 to 6.3 hours, and persisted for 14 and 24 hours, respectively. Circulating granulocytes (neutrophils and bands) increased in a dose-dependent manner, as 11 of 13 patients who received greater than or equal to 1.0 microgram/kg/d responded with a two- to 194-fold increase. Although the neutrophils usually returned to pretreatment levels shortly after stopping GM-CSF, two patients continue to exhibit an elevation of neutrophils for 6 months. Dose-related increases in circulating monocytes and eosinophils were also noted. Transient increases in platelet and reticulocyte counts were observed in two and three patients, respectively. Five of the 16 patients later received maintenance GM-CSF at 3 micrograms/kg/d for 2 to 9 weeks. All showed a dramatic increase in neutrophils after 2 weeks. Thereafter, despite continued therapy, the neutrophil count in four patients declined markedly. In conclusion, GM-CSF is well tolerated by the SC route and induces striking, but usually temporary, improvement in the neutropenia of MDS. Larger prospective phase III trials will determine the duration of hematologic responses and the impact on infection, morbidity, and mortality.
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PMID:Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. 265 78

Treatment with GM-CSF or G-CSF is becoming widely used in patients with chronic neutropenia, or who are aplastic following chemotherapy or autologous or allogeneic bone marrow transplantation. Recently, some authors have described a phenomenon analogous to cyclic agranulocytosis following treatment with G-CSF in a patient with chronic neutropenia. We wish to describe the same phenomenon in a patient with chronic granulocytic leukemia who received GM-CSF (Sandoz) after T cell depletion in order to accelerate hematological reconstitution.
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PMID:Transient cyclic neutropenia following GM-CSF in a patient with chronic granulocytic leukemia transplanted with HLA-identical T cell-depleted donor bone marrow. 267 45

High doses of melphalan cause severe neutropenia and may irreversibly damage hematopoietic stem cells. Treatment of mice with recombinant murine GM-CSF (GM-CSF) for 5 days immediately after 400 micrograms of melphalan did not prevent the severe neutropenia. However, GM-CSF accelerated the neutrophil recovery and reduced the mortality rate during the neutropenic period compared to melphalan-only treated mice. CFU-GM levels measured 6 d after melphalan treatment without GM-CSF were markedly reduced in the bone marrow while being elevated in the spleen. In comparison, GM-CSF further reduced the total CFU-GM population in melphalan-treated mice including the levels in the bone marrow and in the spleen. On d 14 after melphalan, the spleen regained its active CFU-GM production. By d 90, the number of circulating neutrophils, the number of bone marrow CFU-GM and splenic CFU-GM were the same in GM-CSF-treated and -untreated mice. The results suggest that GM-CSF could be used to shorten the neutropenic period and reduce mortality caused by a high dose of melphalan. Though this effect could be at the expense of a temporary reduction in CFU-GM population, GM-CSF did not induce more long-term damage to myelopoiesis than that already caused by melphalan alone.
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PMID:Effect in vivo of recombinant GM-CSF on neutropenia and survival in mice treated by high-dose melphalan. 268 May 79

Human monocytic colony-stimulating factor (hM-CSF) is a glycoprotein which stimulates monocyte production in the bone marrow. It enhances CSF (such as G- and GM-CSF) production of monocytes and megakaryocyte-potentiating activity (Meg-POT). It also enhances tumor-killing activity of monocytes against several leukemic cell lines such as K562, U937, HL60 and Daudi. In the clinical studies, it was shown that hM-CSF infusions accelerated the recovery from neutropenia as well as thrombopenia after anticancer chemotherapy against hematological, gynecologic and urogenital malignancies. Human M-CSF infusions were tolerable without any serious side effects. It is reported that infusions of G-CSF and GM-CSF cause the increment of leukemic cell counts in some cases, but hM-CSF infusions did not increase leukemic cell counts. These results indicate that hM-CSF may be potentially useful for the treatment of myelosuppression induced by cancer chemotherapy in cancer patients.
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PMID:[Human monocytic colony-stimulating factor]. 268 18

Colony-stimulating factors (CSFs) are a family of regulatory glycoprotein hormones that promote the proliferation and differentiation of hemopoietic progenitor cells and augment the functions of mature effector cells in vitro. The recent cloning of human genes and the availability of sufficient quantities of recombinant purified growth factors have made it possible to evaluate their therapeutic potential in cytopenic states. Initial studies with GM-CSF have demonstrated its ability to increase neutrophil, monocyte, and eosinophil counts in patients with acquired immune deficiency syndrome (AIDS), myelodysplastic syndrome (MDS), and aplastic anemia. Both GM-CSF and G-CSF reduce the duration of neutropenia following chemotherapy and accelerate hematopoietic recovery in patients undergoing intensive chemotherapy and autologous bone marrow transplantation. Studies are now ongoing to determine the optimal dose, route, schedule of administration, and long-term effects. While the appropriate settings for the use of different CSFs remain to be determined, the initial results of clinical trials are of great interest and suggest that hematopoietic growth factors will play an important role in several clinical arenas.
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PMID:Clinical applications of colony-stimulating factors. 268 11

Clinical usefulness of G-CSF, GM-CSF and M-CSF was summarized. These CSFs had been demonstrated to accelerate the recovery from neutropenia after anti-cancer chemotherapy and bone marrow transplantation. CSFs were also effective in some patients with aplastic anemia, myelodysplastic syndrome (MDS) and idiopathic neutropenia among children. An increase of neutrophils was observed in these patients responding to CSFs. Few patients with aplastic anemia and MDS, however, responded to G-CSF with an increase of reticulocytes and thrombocytes in addition to neutrophils. Combination of G-CSF with anti-leukemic agents for the treatment of refractory and relapsed acute non-lymphocytic leukemia (ANLL) or as the conditioning for bone marrow transplantation to refractory ANLL patients was found to be quite effective. Possible usage of GM-CSF and M-CSF for cancer treatment by stimulating anti-cancer functions of monocytes-macrophages was also discussed. Furthermore, GM-CSF and M-CSF were demonstrated to decrease serum cholesterol level in rabbits as well as in patients. Possible mechanism of this cholesterol-lowering effect was also discussed.
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PMID:[Colony stimulating factor]. 281 7

Recent progress in molecular cloning has provided access to several major human colony-stimulating factors - GM-CSF, IL-3, G-CSF and M-CSF. Now they are available highly purified from different expression systems (e.g. yeast, E. coli, CHO cells). These molecules, acting multifunctionally in the hematopoietic system, are responsible for proliferation and differentiation of bone marrow-derived progenitor cells in vitro. First clinical studies performed with colony-stimulating factors have shown that neutropenia caused by drug-induced immunosuppression in patients with refractory cancer or autologous bone marrow transplantation was reversed using rh GM-CSF or rh G-CSF. We have investigated the effect of the consecutive administration of rh IL-3 and GM-CSF on hematopoiesis in normal cynomolgus monkeys. Whereas administration of rh IL-3 alone did not result in an increase of WBC counts, the combination therapy of rh IL-3 followed by rh GM-CSF exhibited significant synergistic effects and raised WBC numbers. Furthermore, application of both factors resulted in a platelet rise not seen when one of the factors was used alone. The response was dose dependent and implicated that the therapeutical potential of rh GM-CSF could be expanded if used in combination with rh IL-3.
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PMID:Human recombinant derived IL-3 and GM-CSF in hematopoiesis of normal cynomolgus monkeys. 307 38


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