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)

Clonality of marrow hematopoietic progenitor cells in myelodysplastic syndromes (MDS) was analyzed by X-chromosome inactivation pattern using polymerase chain reaction (PCR). Five female patients were included in this study; two with refractory anemia (RA) and three with RA with excess blasts (RAEB). They were heterozygous for BstXI restriction fragment length polymorphisms (RFLP) of the X-chromosome-linked phosphoglycerate kinase (PGK) gene. In each patient, erythroid and nonerythroid colonies, grown in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF), exhibited no remarkable difference in clonal constitution. Two patients showed only one methylation pattern, suggesting the monoclonal origin of hematopoietic progenitor cells. Colonies of two other patients exhibited predominant and minor methylation patterns in PGK gene, indicating that nonclonal progenitor cells remain a minor population. The bone marrow of one patient appeared to contain a greater proportion of nonclonal progenitors. Stem cell factor (SCF), a potent colony-stimulating factor, enhanced both erythroid and nonerythroid colony formation. However, it did not notably alter the clonal constitutions. We conclude that nonclonal hematopoietic progenitor cells can persist in a substantial number of MDS patients.
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PMID:Evidence for nonclonal hematopoietic progenitor cell populations in bone marrow of patients with myelodysplastic syndromes. 751 21

Using clonogenic assay we investigated the effect of stem cell factor (SCF) on the in vitro growth of clonogenic precursor cells from acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in the presence or absence of recombinant human erythropoietin (rhEpo) or recombinant human granulocyte colony-stimulating factor (rhG-CSF). SCF as a single factor did not induce significant colony formation, and even in the presence of rhEPO or rhG-CSF it very weakly stimulated erythroid colony formation and was rarely capable of inducing myeloid colony formation by clonogenic leukemic cells. In culture dishes supplemented with SCF, both myeloid and erythroid colony formations were dramatically enhanced in MDS, regarding both colony number and size. Colony-formation abilities by MDS progenitors were improved following costimulation with SCF and rhEpo. These results suggest that SCF may have a therapeutic role in restoring hematopoiesis in patients with MDS.
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PMID:Effect of stem cell factor (c-kit ligand) on clonogenic leukemic precursor cells: synergy with other hematopoietic growth factors. 752 82

To investigate the role of colony stimulating factors (CSFs) in the proliferation and differentiation of progenitor cells from myelodysplastic syndromes (MDS), marrow progenitor cells from 18 MDS patients were highly purified using CD34 monoclonal antibody and immunomagnetic microspheres (MDS CD34+ cells). These cells were cultured in serum-free medium with various combinations of five colony stimulating factors (CSFs): recombinant human interleukin-3 (rIL-3), granulocyte/macrophage-CSF (rGM-CSF), granulocyte-CSF (rG-CSF), macrophage-CSF (rM-CSF), and erythropoietin (rEP). Among the tested CSFs, such as rM-CSF, rG-CSF, rGM-CSF and rIL-3, a combination of the first three CSFs was the most effective stimulus for the proliferation of non-erythroid MDS progenitor cells. An increase of undifferentiated "blast" cell colonies in 5/18 MDS patients occurred and these 5 patients belonged to the high-risk group. In the presence of these three CSFs, rIL-3 had no effect on the proliferation and differentiation of MDS CD34+ cells; however, IL-3 was efficient for the proliferation of MDS CD34+ cells to the erythroid lineage. rGM-CSF or rIL-3 alone did not efficiently support proliferation and differentiation of CD34+ cells. M-CSF is present in normal human serum at a concentration of 550 +/- 110 U/ml, a concentration exceeding that used in this study (100 U/ml). Therefore, in vivo administration of G-CSF combined with GM-CSF to MDS patients may be one of the most effective CSF combinations for proliferation of MDS progenitor cells to the non-erythroid lineage. However, the effect on the capacity for differentiation was minimal, especially in patients belonging to the high-risk group.
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PMID:Proliferation and differentiation of myelodysplastic CD34+ cells in serum-free medium: II. Response to combined colony-stimulating factors. 753 45

Differentiation induction therapy is used in myelodysplastic syndromes (MDS) to improve maturation defects and to restore impaired function of malignant cells. To this end, 18 patients with MDS received either a combination therapy consisting in study 1 of all-trans retinoic acid (ATRA) and granulocyte-colony stimulating factor (G-CSF), or in study 2 of a combination with ATRA, G-CSF, erythropoietin (Epo) and tocopherol. The ANC increased in 19/20 patients in both studies, whereas an increase in haemoglobin concentration, platelet counts or reduction of transfusion requirement was seen in only 8/20 patients, correlating strongly with good BFU-E growth (P < 0.001). To assess the role of accessory cells in the modulation of the haemopoietic response to treatment, we analysed the capacity of peripheral blood monocytes to secrete cytokines (IL-1 beta, IL-6, IL-8, TNF alpha). Secretion of all cytokines was significantly reduced before therapy when compared with healthy controls, but increased during therapy, reaching normal levels for IL-8. These data indicate that a combination therapy with ATRA and cytokines improves impaired cytokine secretion from monocytes and induces a multilineage clinical response in a subgroup of MDS patients characterized by an almost intact erythroid compartment. In contrast, induction of TNF alpha might be responsible for treatment failure.
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PMID:Changes in erythroid progenitor cell and accessory cell compartments in patients with myelodysplastic syndromes during treatment with all-trans retinoic acid and haemopoietic growth factors. 855 92

We have previously reported that serum stem factor (SCF) levels are significantly lower in patients with myelodysplastic syndrome (MDS) than normal controls. We have now studied the effects of adding SCF to cultures of blood mononuclear cells from patients with MDS and normal subjects. Three of 17 patients with MDS showed marked increases in erythroid colony numbers with SCF + erythropoietin compared to interleukin-3 + erythropoietin. In two cases (1RA and 1ISA) the erythroid colony numbers became normal. The same RA patient also showed a marked increase in myeloid colony numbers, which were undetectable with granulocyte-macrophage colony-stimulating factor alone, but within the normal range when SCF was added. A fourth patient (ISA) showed a 4.7-fold increase in myeloid colonies with SCF, but no erythroid response. The normal subjects showed a trend towards increased numbers of myeloid colonies with SCF; erythroid colonies did not increase. A correlation was found between the MDS patients' haemoglobin levels and erythroid colony numbers with and without SCF, but there was no correlation between erythroid or myeloid colonies in the presence of SCF and their serum SCF level.
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PMID:Responsiveness to stem cell factor (SCF) of peripheral blood colony-forming cells from patients with myelodysplastic syndromes (MDS). 754 50

Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients. Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemodynamics adversely or to precipitate the onset of end-stage renal failure. Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery. Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects. Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epoetin alfa. A review of its clinical efficacy in the management of anaemia associated with renal failure and chronic disease and its use in surgical patients. 757 84

Steel factor (SLF, c-kit ligand), a potent costimulating cytokine in vitro for myeloid progenitor cells from normal donors, is currently being evaluated in clinical trials for effects on hematopoiesis. Based on a preliminary observation that colony-stimulating factor (CSF)-responsive myeloid progenitor cells (CFU-GM) from a few patients with acute myeloid leukemia (AML) did not respond to the costimulating effects of SLF, we evaluated responsiveness of bone marrow or blood CFU-GM from 26 patients with either AML, chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS) to the effects in vitro of SLF and/or granulocyte-macrophage CSF (GM-CSF). Cells from all 26 patients responded to the stimulating effects of GM-CSF, but marked heterogeneity was detected in each disease category to the costimulating effects of SLF. Nine of 13 patients with AML, 2 of 6 patients with CML and 4 of 7 patients with MDS had clonogenic cells that did not respond significantly to the costimulating effects of SLF. In a more limited study of cells from patients with MDS, it was noted that if the CFU-GM of that patient did not respond to SLF enhancement of CSF-induced colony formation, neither did the erythropoietin (Epo)-dependent erythroid (BFU-E) or multipotential (CFU-GEMM) cells of that patient (3 cases of refractory anemia [RA] evaluating bone marrow and in 1 case blood progenitors as well). If CFU-GM responded, BFU-E and CFU-GEMM responded (bone marrow from 1 patient with chronic myelomonocytic leukemia [CMMol]). Clinical criteria did not readily distinguish between patients who had SLF-responsive vs. -nonresponsive clonogenic cells. While the mechanistic reason for this heterogeneity in responsiveness is not clear, these differences should be carefully considered for possible clinical trials with SLF in patients with acute and chronic myeloid leukemia and MDS.
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PMID:Differential responses of myeloid progenitor cells from patients with myeloid leukemia and myelodysplasia to the costimulating effects of steel factor in vitro. 768 84

The presence of serum or contaminant cells may alter clonal development of haematopoietic progenitor cells in vitro. To investigate the pathogenesis of myelodysplastic syndromes (MDS), marrow progenitor cells from 13 MDS patients were highly purified using monoclonal antibodies including CD34 and immunomagnetic microspheres. The cells positive for CD34 in the purified cells were in the range from 87% to 98%. These purified cells were cultured in serum-free medium with individual colony stimulating factors (CSFs) to investigate whether CD34+ cells from MDS patients have abnormal responses to individual CSFs. Dose response experiments with the purified CD34+ cells and recombinant human macrophage-CSF (rM-CSF), granulocyte-CSF (rG-CSF), granulocyte/macrophage-CSF (rGM-CSF), interleukin-3 (rIL-3) or erythropoietin (rEP) were performed in serum-free fibrin clots in 11 patients. Five patients showed a diminished response to rG-CSF and one patient to rEP. In the remaining six patients the purified CD34+ cells did not respond to a stimulation of any individual CSFs. The results indicate that the progenitor cell growth abnormalities in these disorders involve a defect in the capacity of progenitor cells to respond to stimulation with G-CSF, and present direct evidence for the manner in which myelodysplastic CD34+ cells are impaired.
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PMID:Proliferation and differentiation of myelodysplastic CD34+ cells in serum-free medium: response to individual colony-stimulating factors. 768 82

We treated myelodysplastic syndrome patients (MDS) with both recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (EPO) to determine whether such combination therapy resulted in improvement of their anemias. Twenty-four of 28 patients begun on study completed the protocol and were evaluable for erythroid responses. Therapy was initiated with G-CSF at 1 micrograms/kg administered by daily subcutaneous injection and adjusted to either normalize or double the neutrophil count. EPO was then administered by daily subcutaneous injection at a dose of 100 U/kg and dose-escalated to 150 and 300 U/kg every 4 weeks while continuing the G-CSF. Changes in absolute reticulocyte count, hematocrit level, and need for RBC transfusions were compared with pretreatment values as well as other blood cell counts. Ten of 24 patients (42%) had erythroid responses, whereas all patients had neutrophil responses. Six previously transfused patients no longer required RBC transfusions during the treatment period. Erythroid responses were found to be independent of patient age, French-American-British subtype, duration of disease, prior RBC transfusion requirements, or cytogenetic abnormalities at presentation. Pretreatment serum EPO levels were lower in erythroid-responding as compared with nonresponding patients (median 157 v 600 U/L; P = .05). The combined treatment modality was generally well tolerated. We conclude that a substantial percentage of MDS patients had both erythroid and myeloid responses when treated with the combination of G-CSF and EPO.
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PMID:Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. 752 Jul 83

The role of erythropoietin in the pathogenesis of anaemia associated with inflammatory disorders is unclear. We studied serum erythropoietin levels in patients with inflammatory process of varying aetiologies. Serum erythropoietin levels and reticulocyte counts were prospectively measured in 40 patients with inflammatory syndromes and compared with values obtained in 20 patients with myelodysplastic syndromes. Significant inverse correlation between erythropoietin levels and haemoglobin concentration were noted in the 2 groups. The slope of the regression line for patients with inflammatory disorders was lower as compared with that for the myelodysplastic syndromes. In all cases, when the erythropoietin response in relation to degree of anaemia is compared with that which occurs in patients with myelodysplastic syndromes, the inadequate erythropoietin response in patients with chronic inflammatory process becomes evident. In patients with inflammatory process, a relationship between erythropoietin levels and reticulocyte counts were only noted in patients with mildly anaemia (haemoglobin concentration higher than 10.5 g/dl). This study suggests blunted erythropoietin production and impaired marrow response to this hormone in the anaemia which occurs in inflammatory syndromes and supports the hypothesis that these disorders may contribute to the development of the anaemia associated with inflammatory disorders.
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PMID:Serum erythropoietin and reticulocyte counts in inflammatory process. 774 3


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