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)

C-mpl ligand acts primarily as a lineage-specific hematopoietic growth factor by promoting proliferation of megakaryocyte precursors and their differentiation into megakaryocytes and platelets. In addition to the ability of c-mpl ligand to support megakaryocytic development from CD34+ precursor cells, several lines of evidence also point to a stimulatory effect on hematopoietic stem cells. When recombinant thrombopoietin or pegylated megakaryocyte growth and development factor is administered to normal animals or humans, there is a dose-dependent increase in the platelet count. When administered following chemotherapy in animal models or humans, c-mpl ligands reduce the duration and sometimes the degree of thrombocytopenia. The issue of whether clinically relevant thrombocytopenia can be ameliorated has so far been more difficult to resolve. Because severe thrombocytopenia is not commonly seen with standard chemotherapy regimens, clinical studies examining c-mpl ligands for their ability to ameliorate chemotherapy-induced thrombocytopenia will focus on treatment of acute leukemias and bone marrow transplantation. The potential utility of c-mpl ligands for treatment of myelodysplastic syndromes, aplastic anemias, or in HIV infection, will have to be evaluated in the future. Possibly the greatest potential of thrombopoietic growth factors in the near future may be in transfusion medicine, to collect and to store platelets from healthy donors or in autologous settings.
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PMID:Memorial lecture. Megakaryocytic growth factors: is there a new approach for management of thrombocytopenia in patients with malignancies? 1023 62

The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by peripheral blood cytopenias with a hypercellular bone marrow exhibiting dyspoiesis. The MDS range from those with a relatively indolent course (e.g., refractory anemia with or without ringed sideroblasts) to more aggressive disorders (e.g., refractory anemia with excess blasts [RAEB], and RAEB in transformation [RAEB-T]), which may exhibit a clinical course indistinguishable from acute myeloid leukemia (AML). Supportive care is the standard treatment for most patients, particularly those who are elderly, with the judicious use of blood components and antibiotics. For younger patients with RAEB and RAEB-T, antileukemic therapy might be considered, since the outcome is similar to that of patients with AML. Promising new chemotherapy agents currently in clinical trials include the topoisomerase I inhibitor, topotecan. The only curative treatment for MDS is allogeneic bone marrow transplantation, with long-term survival in approximately 40%, but with treatment-related deaths in 25%-40%. Factors predicting outcome include age, cytogenetics, number of blasts, and others. Myeloid growth factors (e.g., G-CSG, GM-CSF), increase the granulocyte count in most patients and may be useful in the setting of an active infection, although the prophylactic use of these agents does not improve survival. Erythropoietin increases the hematocrit in about 20% of patients. Growth factors being evaluated for their role in enhancing platelet counts include interleukin 11, stem cell factor, and megakaryocyte growth and development factor (thrombopoietin). Newer strategies to improve the outcome of patients with MDS should be based on an increased understanding of the biology of these disorders.
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PMID:The Myelodysplastic Syndromes. 1038 27

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) can stimulate megakaryopoiesis in vitro in some myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) patients. We assessed PEG-rHuMGDF combined with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin 3 (IL-3), IL6, stem cell factor (SCF) or erythropoietin in 40 MDS, 33 AML and 16 normal bone marrow samples. CD61-positive cells in suspension cultures increased with PEG-rHuMGDF alone in 20/25 RA + RAS, 11/14 RAEB + RAEBt and 29/33 AML cases. Further increases when IL-3 and/or SCF were added to PEG-rHuMGDF occurred in 14/20 RA + RAS, 8/13 RAEB + RAEBt and 18/26 AML cases. CFU-Mk growth was poor overall, but could be enhanced by PEG-rHuMGDF combinations in some patients. Stimulation of megakaryopoiesis by PEG-rHuMGDF can be augmented by IL-3 and SCF in many MDS and AML patients.
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PMID:Megakaryopoiesis in vitro in myelodysplastic syndromes and acute myeloid leukaemia: effect of pegylated recombinant human megakaryocyte growth and development factor in combination with other growth factors. 1079 78

Since the purification of thrombopoietin 6 years ago, c-Mpl ligands such as recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) have undergone extensive clinical investigation. Both recombinant forms have been shown to reduce the thrombocytopenia associated with nonmyeloablative chemotherapy. Several areas of research have been identified for further clinical development of c-Mpl ligands. One future direction is to continue to explore the intravenous route of administration of rhTPO and PEG-rHuMGDF, as well as fusion proteins of interleukin-3-thrombopoietin and thrombopoietin peptide mimetics, which may be as potent as thrombopoietin, but may lack antigenicity. Another focus would be on the use of these molecules in treating non-chemotherapy-induced thrombocytopenia associated with myelodysplastic syndrome (MDS), idiopathic thrombocytopenic purpura (ITP), human immunodeficiency virus (HIV)-related ITP, and liver disease. Additionally, c-Mpl ligands may have a role in improving apheresis yields when administered to normal platelet donors. Considerable data demonstrate the effectiveness of PEG-rHuMGDF in raising the platelet yields in apheresis donors. In the past few years, investigation into the use of thrombopoietin for ex vivo expansion of pluripotent stem cells has been extensive. Last, thrombopoietin may serve as a radioprotectant by preventing radiation-induced apoptosis of pluripotent stem cells. In the coming years, the clinical role of rhTPO, PEG-rHuMGDF, and related molecules such as the thrombopoietin peptide mimetics will probably be established for both chemotherapeutic and nonchemotherapeutic indications.
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PMID:Future directions with platelet growth factors. 1083 Dec 88

After the cloning of thrombopoietin (c-mpl ligand, Tpo) in 1994, 2 recombinant thrombopoietic growth factors, full-length glycosylated recombinant human Tpo (reHuTPO) and polyethylene glycol conjugated megakaryocyte growth and development factor (PEG-reHuMGDF), have been studied in humans in a variety of clinical settings. Both thrombopoietins are generally well tolerated if administered intravenously (IV). The c-mpl ligands produce a dose-related enhancement of platelet levels, reduce nonmyeloablative chemotherapy-induced mild thrombocytopenia, and mobilize hematopoietic progenitors. On September 11, 1998, the development of PEG-reHuMGDF was suspended in the U.S., due to formation of the neutralizing anti-Tpo antibody. Those neutralizing antibodies lead to thrombocytopenia and pancytopenia in some patients receiving subcutaneous (SC) PEG-reHuMGDF. Japanese investigators indicate that the probability of antibody formation against PEG-reHuMGDF is low when the drug is administered IV instead of SC. reHuTPO has a more favorable safety profile from the point of antibody production. The c-mpl ligands can improve apheresis yields when administered to normal platelet donors. Preliminary data about the use of PEG-reHuMGDF in myelodysplasia, aplastic anemia, and immune thrombocytopenic purpura are promising. Tpo is usually not effective in myeloablative thrombocytopenia when bone marrow hematopoietic progenitors are not present. The major obstacle for the thrombopoietins is their delayed action for managing clinical thrombocytopenia. This review will focus on the biologic basis, current clinical experience, and future directions for the use of thrombopoietic molecules as drugs. The identification of a safe, effective, and potent pharmacologic platelet growth factor could significantly improve the management of thrombocytopenia-induced bleeding.
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PMID:Thrombopoietin as a drug: biologic expectations, clinical realities, and future directions. 1236 Nov 96

Thrombocytopenia is a common medical problem for which the main treatment is platelet transfusion. Given the increasing use of platelets and the declining donor population, identification of a safe and effective platelet growth factor could improve the management of thrombocytopenia. Thrombopoietin (TPO), the c-Mpl ligand, is the primary physiologic regulator of megakaryocyte and platelet development. Since the purification of TPO in 1994, 2 recombinant forms of the c-Mpl ligand--recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)--have undergone extensive clinical investigation. Both have been shown to be potent stimulators of megakaryocyte growth and platelet production and are biologically active in reducing the thrombocytopenia of nonmyeloablative chemotherapy. However, neither TPO has demonstrated benefit in stem cell transplantation or leukemia chemotherapy. Other clinical studies have investigated the use of TPO in treating chronic nonchemotherapy-induced thrombocytopenia associated with myelodysplastic syndromes, idiopathic thrombocytopenic purpura, thrombocytopenia due to human immunodeficiency virus, and liver disease. Based solely on animal studies, TPO may be effective in reducing surgical thrombocytopenia and bleeding, ex vivo expansion of pluripotent stem cells, and as a radioprotectant. Ongoing and future studies will help define the clinical role of recombinant TPO and TPO mimetics in the treatment of chemotherapy- and nonchemotherapy-induced thrombocytopenia.
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PMID:Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. 1241 15

To evaluate a potential therapeutic role for megakaryocyte growth and development factor (MGDF) in myelodysplastic syndromes (MDS) we compared the in vitro response of normal and myelodysplastic megakaryopoiesis to MGDF on bone marrow mononuclear cells from nine MDS patients and four healthy donors in a short term liquid culture system. The cells were incubated with MGDF alone (1 ng/ml, 10 ng/ml and 100 ng/ml) and in combination with 20 ng/ml stem cell factor, 2 U/ml erythropoietin (EPO) and 100 ng/ml interleukin-3 (IL-3). Cytospins were prepared after 4 days and 10 days for CD61 APAAP staining. In addition, the ploidy of propidium iodide stained CD61 positive cells were detected by flow cytometry. The CD61+ cell number significantly increased (13-fold after 4 days, 56-fold after 10 days of culture) when MGDF (100 ng/ml) was added to the normal bone marrow (NBM) cultures (P=0.0003; P=0.0001). In the MDS cultures the absolute number of endomitotic cells as well as the percentage of polyploid cells remained significantly lower than in NBM after 10 days (P=0.0001). The effect of MGDF on polyploidization of MDS cells was significantly dose dependent (P=0.0051). We found no correlation between peripheral platelet count, cellularity of the bone marrow, number of bone marrow megakaryocytes or FAB-subtype and response to MGDF. Additional administration of IL-3 resulted in a left-shift of megakaryopoiesis in both groups. Even though the response of myelodysplastic megakaryocytic progenitors to MGDF shows inter-individual variations, it is significantly impaired overall. Our data suggest that higher doses of MGDF may be able to ameliorate thrombocytopenia in a subgroup of MDS patients.
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PMID:In vitro response of myelodysplastic megakaryocytopoiesis to megakaryocyte growth and development factor (MGDF). 1248 65

To date, there are no curative therapeutic options for patients with myelodysplastic syndromes (MDS) other than allogeneic stem cell transplantation. We treated an MDS patient with 10 microg/kg pegylated recombinant human megakaryocyte growth and development factor (rHuMGDF) for more than 450 d. The patient's platelet counts increased from <10 x 10(9)/l to 50 x 10(9)/l. Interestingly, haemoglobin levels increased dramatically and reached over 13 g/dl without additional transfusion. Adverse events and neutralizing antibodies were not observed during treatment, suggesting that the long-term administration of rHuMGDF might be of clinical benefit to patients with MDS.
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PMID:Long-term administration of pegylated recombinant human megakaryocyte growth and development factor dramatically improved cytopenias in a patient with myelodysplastic syndrome. 1518 Aug 75

Since thrombopoietin (TPO) was cloned in 1994, TPO receptor (TPO-R) agonists have been developed which have shown significant clinical activity in various conditions characterized by thrombocytopenia. First-generation TPO-R agonists were recombinant forms of human TPO. The clinical development of these molecules was discontinued after one of them, pegylated recombinant human megakaryocyte growth and development factor, was associated with the development of neutralizing autoantibodies cross-reacting with endogenous TPO. Second-generation TPO-R agonists are now available, which present no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have been granted marketing authorization for use in patients with primary immune thrombocytopenia unresponsive to conventional treatments. Clinical trials with TPO-R agonists are also ongoing in other thrombocytopenias, such as hepatitis C virus-related thrombocytopenia and the myelodysplastic syndromes.
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PMID:New thrombopoietin receptor agonists for platelet disorders. 2253 71

The two generations of thrombopoietin (TPO) receptor (R) agonists have had utility in a number of hematologic conditions. However their use has often been surprisingly complex and drawbacks have been revealed in certain conditions more than in others. The first-generation megakaryocyte growth and development factor (MGDF) was discontinued due to the production of antibodies against it that cross-reacted with native TPO. Nonetheless it was tested in a wide variety of thrombocytopenic conditions and showed unequivocal efficacy in increasing the number of platelets in certain ones. As a result of lessons learned with MGDF, second-generation TPO-R agonists romiplostim and eltrombopag were initially tested and have been approved for the treatment of chronic immune thrombocytopenia (ITP), thrombocytopenia in hepatitis C, and recently aplastic anemia. These agents have had more mixed outcomes in diseases such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Results of several studies will be discussed.
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PMID:The new thrombopoietic agenda: impact on leukemias and MDS. 2545 80


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