Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

As part of a broad phase I study of recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF), four patients were treated who had myelodysplastic syndrome (MDS) with excess blasts. The GM-CSF was given daily as an intravenous injection over a period of 30 min for 5 days. A total of 11 cycles were conducted. Each patient received at least two different dose levels. In three patients, three different dosages were delivered. The treatment course was interrupted by a 10-day rest period. Rh GM-CSF was well tolerated, with only minor side effects seen, which included bone discomfort at the lower back, sternum and ribs, and constitutional symptoms such as low grade fever, nausea/vomiting, and mild myalgias. Whereas no increases in platelet and reticulocyte counts were recorded, elevations of absolute neutrophil counts above 100 cells/microliters occurred in all patients. The most striking finding was, however, the development of increases in the number of circulating and bone marrow blast counts that were observed particularly when doses of greater than or equal to 500 micrograms/m2 of body surface area were administered. In line with data demonstrating in vitro induction of proliferation of leukemic blast cells by rh GM-CSF, one may take advantage of blastogenesis induced in vivo that may favor the use of a therapeutic strategy by recruiting quiescent cells into the mitotic cycle which would then represent optimum targets for a subsequent cycle-specific cytotoxic chemotherapy. Such an approach could form the basis for new clinical trials in MDS.
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PMID:Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome with excess blasts. 265 95

The in vitro effect of recombinant human GM-CSF (rHuGM-CSF) was tested on bone marrow-derived multilineage (CFU-GEMM) as well as megakaryocytic (CFU-Mk), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitors in a group (n = 16) of patients with myelodysplastic syndromes (MDS). Hematopoietic progenitor cell growth was markedly impaired in MDS patients as compared to normal controls (p less than 0.05, at least). Recombinant HuGM-CSF supported the growth of CFU-GEMM, CFU-Mk, and BFU-E at lower, equivalent, or slightly higher frequencies that those found in cultures plated with medium conditioned by peripheral blood leukocytes (PHA-LCM), but it was invariably ineffective in improving growth values. Recombinant HuGM-CSF supported the growth of granulocyte-macrophage colonies in 15 of 16 cases. The overall incidence (mean +/- SEM) of CFU-GM in cultures containing rHuGM-CSF (5 ng/ml) was significantly higher than the one found in cultures stimulated with PHA-LCM (40 +/- 15 vs. 17 +/- 7, p less than 0.05). Upon culture with rHuGM-CSF (5 ng/ml), in 5 of 15 patients de novo colony formation was observed (8 +/- 4) and in 4 of 15 patients CFU-GM growth (129 +/- 33) fell within normal range. Doses of rHuGM-CSF higher than 5 ng/ml did not result in a further increase of MDS-derived colony formation. It is concluded that rHuGM-CSF (a) does not improve the growth of CFU-GEMM, CFU-Mk, and BFU-E; (b) may completely restore the growth of CFU-GM in a subgroup of MDS patients; (c) while ineffective in improving anemia and thrombocytopenia, its in vivo in MDS may correct leukopenia through an effect at the level of granulocyte-macrophage progenitor cell compartment, at least in a subset of highly responsive patients.
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PMID:Growth of human hematopoietic colonies from patients with myelodysplastic syndromes in response to recombinant human granulocyte-macrophage colony-stimulating factor. 265 96

The conversion of normal haemopoietic stem cells to myelodysplastic and then to leukaemic cells is marked by a number of events leading to progressive genetic changes in the abnormal clonal population. Cytogenetic evidence points to abnormalities at specific chromosomal locations, commonly involving chromosomes 5 and 7, where there are a particular concentration of genes directly involved in the regulation of haemopoietic proliferation and differentiation. These include GM-CSF, IL-3, M-CSF, erythropoietin and others. Other genes that may be involved in the preleukaemic process are so-called 'oncogenes' such as met on chromosome 7q and fms on 5q (which codes for the M-CSF receptor) that may be deleted or translocated. The ras gene family is activated by point mutations in a wide variety of malignant states, including myelodysplasia and acute myeloblastic leukaemia. At the present time we do not know the cause of these genetic lesions, their functional significance or the sequence in which they occur.
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PMID:Oncogenes in the myelodysplastic syndrome. 267 42

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

A 60-year-old patient with a myelodysplastic syndrome (MDS) corresponding to refractory anemia with an increase in blast cells (RAEB) was treated with granulocyte-macrophage colony stimulating factor (GM-CSF) and erythropoietin (EPO) for severe symptomatic pancytopenia. During the GM-CSF treatment a distinct increase in granulocytes was observed, but the reticulocytes and thrombocytes decreased to the point where treatment had to be discontinued after eight days. After subsequent treatment with EPO the reticulocyte count rose from 0% to 2%. However, this rise alone was insufficient to decrease the number of blood transfusions required. The thrombocyte count rose to the original values after the cessation of GM-CSF therapy while continuing treatment with EPO. Bone marrow investigations were performed before and after GM-CSF treatment and indicated a distinct increase in the myeloid precursor cells after therapy, without an increase in blasts. On the other hand, an obvious decrease in erythro- and megakaryopoiesis was observed.
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PMID:[Combined GM-CSF and erythropoietin therapy in myelodysplastic syndrome]. 269 67

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

We have examined the efficacy of various drugs in 44 patients with MDS and found the different effectiveness which depends on the type of MDS. Namely, RA appears to respond to steroid hormone, androgen, and/or vitamin D3, regardless of single or combined use. In particular, it is obvious in androgen, and as our previous reports, high content of acidic ferritin in RBC with RA have changed to more basic ones by treatment with androgen. On the contrary, these drugs were not effective on RAEB, RAEB-T, and CMML. A long-term observation is needed to determine whether the prolonged or decreased occurrence of leukemia could be obtained in the effective cases with RA. Most of the cases who did not develop overt leukemia during this study died of bleeding or infections due to thrombocytopenia or leukocytopenia, thus indicating that supportive therapies are important in patients with MDS. Since it has recently been reported that recombinant G-CSF or GM-CSF is helpful to increase the number of leucocyte and to enhance their functional recovery in MDS, these factors may be powerful agents against infections when they are carefully used with regard to the activation of leukemic clones.
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PMID:[Therapy of the preleukemic state: effect of androgens on refractory anemia]. 283 1

The availability of rh GM-CSF has allowed the in vivo treatment of patients with cytopenia. Therefore a phase I/II trial was initiated to study the effect of rh GM-CSF in patients with myelodysplastic syndromes who were not eligible for other kinds of therapy. rh GM-CSF has been tested in 10 patients in doses from 15 micrograms/m2 to 150 micrograms/m2 given intravenously over 8 hours for a cycle of 7 days followed by an interval of 14 days and a second 7-day treatment course. A dose dependent increase in leukocyte count was observed in 9 out of 10 patients. No change in reticulocyte numbers was seen and only one patient experienced an increase in platelet count. Toxicity mainly consisted of mild local phlebitis at the site of infusion and sternal pain after bolus injection. An increase in blast cell counts in some patients necessitated the start of low dose Ara-C therapy.
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PMID:Phase I/II study with GM-CSF in patients with myelodysplastic syndromes. 307 28

We performed a Phase I/II study of the administration of recombinant human GM-CSF to patients suffering from severe bone marrow failure, either due to aplastic anemia or myelodysplastic syndrome. Doses ranging from 15 micrograms/m2 to 480 micrograms/m2 were administered as an intravenous infusion daily for 7 days. Temporary improvements were seen in granulocyte counts, monocyte counts and reticulocyte counts. There was no reduction in erythrocyte transfusion requirements and no effect was observed on platelet counts. There was only minimal toxicity consisting of transient low back discomfort, anorexia, myalgias/arthralgias, and low grade fever. Our data suggest that prolonged use of GM-CSF might benefit some patients with severe marrow failure.
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PMID:Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in bone marrow failure. 307 31


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