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Cytokine & Growth Factor Reviews Feb 2009Hematopoietic growth factor (HGF) mimetics offer a number of attractive advantages as therapeutic agents. Small chemical compounds, in particular, provide reduced cost... (Review)
Review
Hematopoietic growth factor (HGF) mimetics offer a number of attractive advantages as therapeutic agents. Small chemical compounds, in particular, provide reduced cost and oral availability. As many of these mimetics are unrelated in structure to the normal cytokine the immunogenic response is not a significant issue. Isolation of small peptide agonists for erythropoietin (EPO) and thrombopoietin (TPO) receptors has been associated with significant translational challenges and here we summarize approaches used to achieve the potency and stability required for clinical utility. We also compare and contrast the initial screening approaches, and the translational and clinical issues associated with two recently approved TPO mimetics, romiplostim and the orally available eltrombopag. Finally we summarize the development and clinical findings for the EPO mimetic, Hematide, consider alternative approaches, and discuss the future potential for isolation of growth factor (GF) mimetics.
Topics: Animals; Carrier Proteins; Chemistry, Pharmaceutical; Cytokines; Drug Design; Drug Evaluation, Preclinical; Hematopoietic Cell Growth Factors; Humans; Peptides; Polyethylene Glycols; Purpura, Thrombocytopenic, Idiopathic; Receptors, Erythropoietin; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thrombopoietin
PubMed: 19223217
DOI: 10.1016/j.cytogfr.2009.01.002 -
Cytokine & Growth Factor Reviews Mar 1997BCR/ABL is a human chimeric oncogene that causes chronic myelogenous leukemia (CML). The BCR/ABL oncogene is generated from the Philadelphia chromosome (Ph)... (Review)
Review
BCR/ABL is a human chimeric oncogene that causes chronic myelogenous leukemia (CML). The BCR/ABL oncogene is generated from the Philadelphia chromosome (Ph) translocation, t(9;22)(q34;q11), and creates a constitutively active tyrosine kinase. There is clonal expansion of hematopoietic stem cells of several different lineages in CML. CML patients in stable phase usually have high white blood counts and immature cells of granulocytic lineages. Stable phase CML evolves to a more aggressive phase typically within 3.5-5 years, where differentiation is blocked and acute leukemia ensues. The transition of CML stable phase to blast phase is reflected in the loss of growth factor requirement of CML cells and correlates with additional cytogenetic alterations. Some biological effects reported in primary CML cells include reduced apoptosis and altered adhesion to fibronectin; however, the cells are dependent on hematopoietic growth factors. On a molecular level, the BCR/ABL translocation is well characterized. However, the actual mechanism of transformation by the BCR/ABL oncogene of hematopoietic cells is largely unknown. Enhancement of the c-ABL tyrosine kinase activity in BCR/ABL appears to be crucial for transformation. This tyrosine kinase activity leads to activation of several signal transduction pathways that are also utilized by hematopoietic growth factors, including steel factor, thrombopoietin, interleukin-3, and granulocyte/macrophage-colony stimulating factor. In several model systems, BCR/ABL has overlapping biological effects with hematopoietic growth factors, and transformation of hematopoietic growth factor-dependent cell lines leads to growth factor independence. In this review, we will describe the molecular and biological abnormalities in CML and several signal transduction mechanisms utilized by BCR/ABL as compared to hematopoietic growth factors.
Topics: Adaptor Proteins, Signal Transducing; Cell Adhesion; Cell Transformation, Neoplastic; Fusion Proteins, bcr-abl; Genes, abl; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Biological; Nuclear Proteins; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins; Proto-Oncogene Proteins c-cbl; Signal Transduction; Ubiquitin-Protein Ligases; ras Proteins
PubMed: 9174663
DOI: 10.1016/s1359-6101(96)00047-0 -
International Journal of Cell Cloning Mar 1989Studies of the growth regulation, differentiation and transformation of myeloid cells have been greatly facilitated by the availability of a variety of hematopoietic... (Review)
Review
Studies of the growth regulation, differentiation and transformation of myeloid cells have been greatly facilitated by the availability of a variety of hematopoietic growth factor-dependent cell lines. These cell lines have been isolated from long-term bone marrow cultures and myeloid tumors using interleukin 3 (IL-3) as a growth factor. Using growth factor-dependent cells, it has been shown that growth regulation by IL-3 involves binding to a high-affinity receptor of 140 Kd and activation of tyrosine phosphorylation. IL-3 binding is associated with a number of cellular responses which are required for maintenance of viability, including induction of transcription of the c-myc and ornithine decarboxylase (ODC) genes. In addition, IL-3 regulates the expression of transcription of the gamma T cell receptor locus. The properties of the IL-3-dependent lines are consistent with the hypothesis that they are transformed in their ability to terminally differentiate. In some of the cell lines, this transformation may terminally differentiate. In other of the cell lines, this transformation may be due to the altered expression of the c-myb gene. In other cell lines, transformation is associated with the activation of the expression of a novel gene, termed Evi-1, of the zinc finger family of transcriptional factors. Comparable transformation of erythroid lineage cells is speculated to be due to the activation of the expression of another novel gene termed spi-1. These studies have emphasized the value of well-characterized hematopoietic growth factor-dependent cell lines in advancing our understanding in the basic biology of myeloid cells.
Topics: Animals; Cell Line; Growth Substances; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interleukin-3; Tumor Cells, Cultured
PubMed: 2656885
DOI: 10.1002/stem.5530070202 -
Annals of the New York Academy of... Jun 2001Hematopoietic growth factors are glycoproteins of 15-70 kDa. Although much clinical success has been obtained using recombinant proteins produced in mammalian cell lines...
Hematopoietic growth factors are glycoproteins of 15-70 kDa. Although much clinical success has been obtained using recombinant proteins produced in mammalian cell lines and in microbial fermentation processes, the full-length polypeptides necessarily are expensive to produce, require parenteral administration, and in some cases have provoked detrimental immune responses. With the availability of high throughput biological function and receptor binding assays it has become possible to screen millions, if not billions, of randomly produced organic compounds and relatively short peptides to identify lead compounds for the development of small molecular mimetics of hematopoietic growth factors. Herein the strategies used to screen libraries of small molecules and peptides and the successes in finding mimetics and antagonists for/to erythropoietin, granulocyte colony-stimulating factor, and thrombopoietin are reviewed. Finally, the structural study of mimetic-receptor complexes has provided us with many molecular details of growth factor-induced receptor activation and is likely to yield new insights into the molecular basis of hematopoietic signal transduction.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Bacteriophages; Binding, Competitive; Dimerization; Drug Design; Drug Evaluation, Preclinical; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Mice; Molecular Sequence Data; Neoplasm Proteins; Peptide Library; Peptides; Peptides, Cyclic; Protein Binding; Proto-Oncogene Proteins; Rabbits; Receptors, Cytokine; Receptors, Erythropoietin; Receptors, Granulocyte Colony-Stimulating Factor; Receptors, Thrombopoietin; Reticulocyte Count; Structure-Activity Relationship; Thrombopoietin
PubMed: 11458500
DOI: 10.1111/j.1749-6632.2001.tb03582.x -
Current Opinion in Hematology May 1999The problems of immunologic adaptation during the transitional period from intra- to extrauterine life are responsible for the physiologic immaturity of the immune... (Review)
Review
The problems of immunologic adaptation during the transitional period from intra- to extrauterine life are responsible for the physiologic immaturity of the immune function in newborn infants. In preterm neonates the immunodeficiency is more severe and prolonged and is associated with a higher incidence of infections and sepsis. Furthermore, due to immaturity of the hematologic system, anemia, thrombocytopenia, and neutropenia are frequently observed in very low birth weight infants. The dysregulation of cytokine and hematopoietic growth factor synthesis is an important contributory factor to the complex deficiency of immunologic and hematologic function in the neonate and may explain the reduced incidence of acute graft-versus-host disease observed after cord blood transplantation in children. Human milk is a rich source of most of the cytokines that are reduced in the neonate. Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin are currently under evaluation in newborn infants with septic neutropenia or anemia of prematurity.
Topics: Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Infant, Newborn; Infant, Premature
PubMed: 10226741
DOI: 10.1097/00062752-199905000-00011 -
CA: a Cancer Journal For Clinicians 1996Over the past ten years, the availability of pharmacologic quantities of hematopoietic growth factors has opened many avenues of study in basic science and clinical... (Review)
Review
Over the past ten years, the availability of pharmacologic quantities of hematopoietic growth factors has opened many avenues of study in basic science and clinical investigation. Numerous studies performed to date have demonstrated significant benefits from the use of these cytokines. The side effect profiles, particularly for "later acting" growth factors, indicate that they are generally well tolerated by most patients. The table summarizes the potential indications for hematopoietic growth factor use as discussed in this article, as justified by current evidence of benefit, harm, and cost effectiveness resulting from their use in various clinical settings. It has been clearly demonstrated in standard-dose chemotherapy regimens that these agents shorten the duration of myelosuppression, reduce the incidence of significant infection, can shorten hospital stay, and reduce antibiotic use for most patients, although the cost/benefit ratio for growth factors such as G-CSF makes this a cost-effective approach only for regimens with a high (40 percent or more) incidence of febrile neutropenia. Limited indirect evidence supports the use of growth factors in patients with a prior episode of fever and neutropenia. The suppressive approach to growth factor use could potentially benefit patients with documented infection or clinical deterioration, but it has not otherwise been shown to be a particularly effective or cost-effective approach. Administration of hematopoietic growth factors has been instrumental in facilitating both autologous and allogeneic peripheral progenitor cell mobilization and techniques such as ex vivo expansion. There is an increasing body of data supporting the use of high-dose chemotherapy regimens with progenitor cell rescue for a number of malignancies and limited data supporting the benefits of maintaining dose-intensity for certain malignancies in standard-dose settings. Although of continuing concern, clinically significant evidence of disease stimulation and recurrence has not been unequivocally demonstrated in studies to date. A comprehensive set of evidence-based guidelines has recently been published by the American Society of Clinical Oncology. As often is the case, current studies have perhaps generated more questions than answers. Future investigation will undoubtedly focus on use of hematopoietic growth factors in conjunction with other techniques, such as outpatient-based treatment of febrile neutropenia, CD34-positive stem cell selection in autologous transplantation, selective manipulation of T-cell subsets (to decrease the incidence of severe graft-versus-host disease) in allogeneic transplantation, and high-dose therapy with stem cell transplantation.
Topics: Anemia; Animals; Erythropoietin; GPI-Linked Proteins; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Leukemia; Lymphoma; Membrane Glycoproteins; Mesothelin; Multiple Myeloma; Neoplasms; Proteins
PubMed: 8646546
DOI: 10.3322/canjclin.46.3.165 -
Current Opinion in Hematology May 1994Immunoassays have recently made it possible to specifically measure the circulating levels of hematopoietic growth factors. This is helping us to understand the in vivo... (Review)
Review
Immunoassays have recently made it possible to specifically measure the circulating levels of hematopoietic growth factors. This is helping us to understand the in vivo regulation of hematopoiesis under conditions of steady state or stress, providing insights into the physiological roles of hematopoietic growth factors and their importance in the pathogenesis of disease. As mediators of pathological processes, hematopoietic growth factors may be targets for antagonist therapy in some diseases. Exogenous hematopoietic growth factors may also be useful therapeutically to augment physiological responses, so understanding hematopoietic growth factor regulation and serum levels may assist the development of specific therapies. Hematopoietic growth factor levels may also serve as tumor markers and assist prognostication or monitoring during the clinical course of an illness. The growth factors of particular interest include the four classic colony-stimulating factors: granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and multi-colony-stimulating factor, also known as interleukin-3. Other cytokines with hematopoietic growth factor activity include interleukin-1, interleukin-6, interleukin-11, stem cell factor (also known as Steel factor or mast cell growth factor), and leukemia inhibitory factor.
Topics: Animals; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Leukocytes
PubMed: 9371287
DOI: No ID Found -
Journal of Hematotherapy 1993Newborns are characterized by significant developmental immaturities in hematopoiesis and phagocytic immunity. Defects in myelopoiesis and thrombopoiesis predispose... (Comparative Study)
Comparative Study Review
Newborns are characterized by significant developmental immaturities in hematopoiesis and phagocytic immunity. Defects in myelopoiesis and thrombopoiesis predispose newborns to peripheral cytopenias, especially during states of increased demand. However, committed myeloid (CFU-GM) and megakaryocytic (CFU-Meg) progenitor cells in circulating cord blood are increased compared to that of adult bone marrow and/or adult peripheral blood. This increase in hematopoietic committed progenitor cells has allowed the use of cord blood for hematopoietic reconstitution following myeloablative therapy in transplantation. Decreased production of GM-CSF, G-CSF, and IL-3 has been demonstrated in cord-versus-adult mononuclear cells with a similar decrease in their mRNA transcript expression. Other growth factors, however, including steel factor, are increased in the basal state and further increased during stimulation from umbilical-vein endothelial cells versus adult-aortic endothelial cells. The use of single, sequential, or simultaneous administration of both early- and late-acting hematopoietic growth factors, however, has profound effects in the modulation of neonatal-rat hematopoiesis. The combination of G-CSF and early-acting CSFs, such as steel factor or IL-3, induces a significant increase in peripheral neutrophilia and bone marrow progenitor pools.
Topics: Adult; Animals; Animals, Newborn; Endothelium, Vascular; Fetal Blood; Gene Expression Regulation; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Infant, Newborn; Leukocytes, Mononuclear; Rats; Rats, Sprague-Dawley
PubMed: 7921978
DOI: 10.1089/scd.1.1993.2.217 -
Immunology Series 1990Hemopoietic cells have an absolute requirement for survival and proliferation for specific growth factors. The growth factors maintain the critical vitality of the cells... (Review)
Review
Hemopoietic cells have an absolute requirement for survival and proliferation for specific growth factors. The growth factors maintain the critical vitality of the cells by stimulating adenosine triphosphate (ATP) synthesis and hexose transport. Intracellular alkalinization also occurs rapidly through the stimulation of the Na+/H+ antiporter. These immediate metabolic events, not initiated by serum components, appear to be necessary for the integrity of cellular viability (Fig. 6). Interleukin-3 has been shown to induce the activation of PK-C through a mechanism(s) not requiring the hydrolysis of phosphoinositol 4,5 bisphosphate. A role for Ca2+ influx or intracellular release in the action of CSFs or interleukins has not been shown. Although downregulation of cAMP has been reported in response to IL-2, the signal transduction process of CSFs and IL-2 appears not to be mediated by upregulation of cyclic nucleotide metabolism or "classical" phospholipid degradative pathways. Protein phosphorylation is clearly modulated by the hemopoietic cytokines, yet only the CSF-1 receptor has any known intrinsic kinase activity. Instead, the IL-3, GM-CSF receptors, and perhaps G-CSF appear to be coupling to kinases of both tyrosine and serine specificities. This may be a direct allosteric interaction with membrane-associated kinases or transduced through an intermediate protein such as those using GTP. Such is the case for many hormone receptors that couple to amplifying "second messenger" enzyme systems (i.e., adenylate cyclase, phospholipase C) or members of the insulin growth factor family that couple to tyrosine kinases in proximity to the receptors (IGF-II). One of the kinase systems that IL-2, IL-3, and other CSFs stimulate appears to have some characteristics similar to PK-C. Direct activators of PK-C stimulate some similar serine-threonine phosphorylation and perhaps even tyrosine phosphorylation. The hemopoietic growth factors, however, stimulate tyrosine phosphorylation of some proteins that are not phosphorylated in response to PK-C activators, suggesting that these kinase systems are independently regulated. Although phorbol esters stimulate many of the same metabolic activities (ATP synthesis in myeloid and lymphoid cell lines), growth-factor abrogation is clearly associated with the action of tyrosine kinase oncogenes or the nuclear oncogene effectors such as v-myc. It is likely, therefore, that tyrosine kinases are playing a critical role in the control of proliferation although the dominant amount of cellular protein phosphorylations are on serine. Both classes of kinases are apparently required for growth-factor action. All the hemopoietic growth factors examined thus far stimulate the steady-state accumulation of the nuclear protooncogenes.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Gene Expression Regulation; Hematopoietic Cell Growth Factors; Humans; Phosphorylation; Proteins; Receptors, Colony-Stimulating Factor; Signal Transduction
PubMed: 2090258
DOI: No ID Found -
The biology of stem cell factor, a new hematopoietic growth factor involved in stem cell regulation.International Journal of Clinical &... 1993Recently, a new hematopoietic growth factor, stem cell factor, the ligand for the c-kit-proto-oncogene, has been cloned. The gene for this factor or for its receptor are... (Review)
Review
Recently, a new hematopoietic growth factor, stem cell factor, the ligand for the c-kit-proto-oncogene, has been cloned. The gene for this factor or for its receptor are deleted in two well known series of mice mutants which display pleiotropic stem cell defects. Therefore, this factor supposedly plays an important role in stem cell biology. This paper reviews some of the elegant genetic work which led to the discovery of the factor and of its receptor, the biological effects that this factor exerts in the hematopoietic system in normal individuals and in patients with Diamond-Blackfan anemia and speculates on some of its potential clinical applications.
Topics: Anemia; Animals; Chromosome Mapping; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Mice; Mutation; Proto-Oncogene Mas; Stem Cell Factor
PubMed: 7686057
DOI: 10.1007/BF02592286