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 goal of our study was to identify cytokine combinations that would result in simultaneous ex vivo expansion of both the megakaryocyte (Mk) and granulocyte lineages, since these cell types have the potential to reduce the periods of thrombocytopenia and neutropenia following chemotherapy. We investigated the effects of cytokine combinations on expansion of the Mk (CD41a+ cells and colony forming unit [CFU]-Mk) and granulocyte (CD15+ cells and CFU-granulocyte/monocyte [GM]) lineages. Peripheral blood CD34+ cells were cultured in serum-free medium with interleukin 3 (IL-3), stem cell factor (SCF), and various combinations of thrombopoietin (TPO), IL-6, GM-CSF, and/or G-CSF. The Mk lineage was primarily influenced by TPO in our cultures, although Mk and CFU-Mk numbers were increased when TPO was combined with IL-6. The primary stimulator of the granulocyte lineage was G-CSF, although many synergistic and additive effects were observed with addition of other factors. Expansion of CFU-GM increased upon addition of more cytokines. The cytokine combination of IL-3, SCF, TPO, IL-6, GM-CSF and G-CSF produced the greatest number of granulocytes and CFU-GM. The minimum cytokines necessary for expansion of both the Mk and granulocyte lineages included TPO and G-CSF, since no other factors examined could increase Mk and granulocyte numbers to the same extent. The number of hematopoietic progenitors produced in our culture system should be sufficient for successful engraftment following myelosuppressive therapy if produced on a scale of about one liter.
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PMID:Evaluation of cytokines for expansion of the megakaryocyte and granulocyte lineages. 917 Feb 11

Most studies that use recombinant granulocytopoietic cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), with the intent of attenuating neutropenia generally have delayed the administration of the cytokine until 24 to 72 hours following completion of chemotherapy. This practice was initiated out of theoretic concern that colony-stimulating factor administration may cycle and differentiate a population of normal cells, thus increasing their susceptibility to cycle-specific antineoplastic agents. The theory, in fact, has been substantiated by evidence from several clinical trials of concurrent administration. Thus, simultaneous administration of chemotherapy and G-CSF or GM-CSF should be limited to investigational protocols with scientific objectives, such as cycle compression or malignant cell sensitization.
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PMID:Safety of concomitant use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor with cytotoxic chemotherapy agents. 920 39

The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibody-induced myelosuppression and allow either dose escalation of radio-antibody using 131I, 90Y or 188Re conjugated to either intact antibody or bivalent fragments or more frequent dosing with 131I-IgG. Survival, peripheral blood counts, hematopoietic tissue weight and number of marrow CFCs were used to determine the ability to dose-intensify with a single dose or to reduce the spacing between doses. In this report, we show that in the absence of cytokines, 2 cycles of 131I-IgG spaced at 28, 35, 42 and 49 days resulted in 100%, 100%, 40% and 0% lethality, respectively. In contrast, cytokine intervention reduced lethality to 45%, 20%, 0% and 0% at the same time intervals between doses. Thus, the use of cytokines permits at least a 1 week earlier redosing of 131I-IgG. Cytokine intervention also has reduced the magnitude of myelosuppression, as measured by neutropenia and thrombocytopenia, thus permitting intensification of single doses of radio-iodinated intact antibodies, bivalent fragments and 90Y-IgG by at least 30%, 50% and 25%, respectively. However, cytokines were not effective at permitting dose escalation of either 90Y-F(ab')2 or 188Re-IgG. Further optimization of the dose schedule of cytokine administration needs to be explored for these 2 nuclide-antibody forms.
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PMID:Application of cytokine intervention for improved radio-antibody dose delivery. 921 39

Allogeneic transplantation of cytokine-mobilized peripheral blood stem cells (PBSCs) is now being increasingly performed, but safety considerations for hematologically normal PBSC donors have not been fully addressed. Progenitors are generally mobilized for collection from normal donors using recombinant human granulocyte colony-stimulating factor (rhG-CSF). Although the short-term safety profile of rhG-CSF seems acceptable, experience remains limited and its optimal dose and schedule have not been defined. Minimal data exist regarding long-term safety of rhG-CSF, primarily derived from experience in patients with chronic neutropenia or cancer. An "ad hoc" workshop was recently convened among a group of investigators actively involved in the field of allogeneic stem cell transplantation to discuss the safety issues pertaining to normal PBSC donors. There was agreement on the following points: (1) On the basis of available data, it appears that rhG-CSF treatment and PBSC collection have an acceptable short-term safety profile in normal donors. However, the need for continued safety monitoring was recognized. (2) rhG-CSF doses up to 10 microg/kg/d show a consistent dose-response relationship with the mobilization (and collection) of CD34+ progenitor cells, and this dose is acceptable for routine clinical use. Whether higher doses are superior (or cost effective) remains to be determined, and they may produce more severe side effects. The potential risks of marked leukocytosis (arbitrarily defined as a leukocyte count of more than 70 x 10(9)/L) have been a concern, and rhG-CSF dose reduction is performed by many centers to maintain leukocyte counts below this level. (3) Transient post donation cytopenias, involving granulocytes, lymphocytes, and platelets, may occur and are at least partly related to the leukapheresis procedure. These are generally asymptomatic and self-limited; follow-up blood counts are not necessarily required. Reinfusion of autologous platelet-rich plasma should be considered for donors with expected postdonation thrombocytopenia (platelet count < 80 to 100 x 10(9)/L). (4) Donors should meet the eligibility criteria which apply to donors of apheresis platelets, with the exception that pediatric donors may also be considered. Any deviation from these criteria should have supporting documentation. There is insufficient information at this time to clearly establish definite contraindications for PBSC collection in a hematologically normal donor. Potential contraindications include the presence of inflammatory, autoimmune, or rheumatologic disorders, as well as atherosclerotic or cerebrovascular disease. (5) The creation of an International PBSC Donor Registry is desirable to facilitate monitoring the long-term effects of the procedure. Individual institutions or donor centers are encouraged to establish their own PBSC donor follow-up system, preferably with a standardized approach to data collection.
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PMID:Allogeneic blood stem cell transplantation: considerations for donors. 1084 12

Cytokine profiles were studied during 19 episodes of chemotherapy-induced neutropenia in 17 patients with haematological malignancies. Circulating concentrations of interleukin 1 alpha (IL-1 alpha), tumour necrosis factor alpha (TNF-alpha) and IL-1 receptor antagonist (IL-1ra) were measured before chemotherapy and thereafter three times weekly. During and after chemotherapy no significant changes were found in circulating cytokines. After start of chemotherapy, the ex-vivo LPS-stimulated production of cytokines in whole blood decreased and subsequently disappeared completely in all patients, and recovered after the end of treatment. The decrease of cytokine production could not be attributed to the decreased number of cells only, as the net production per circulating neutrophil or monocyte also decreased significantly, and was restored after completion of chemotherapy. These results show that the production of IL-1 beta, TNF-alpha and IL-1ra in blood disappears during chemotherapy-induced neutropenia, not only due to the decreased number of producing cells, but also as a result of a decreased production per cell, suggesting a mechanism of downregulation.
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PMID:Regulation of the production of pro-inflammatory cytokines and antagonists during chemotherapy-induced neutropenia in patients with haematological malignancies. 932 20

Granulocyte colony-stimulating factor (G-CSF) is a cytokine that stimulates the proliferation and differentiation of hematopoietic progenitor cells committed to the neutrophil/granulocyte lineage. Recombinant G-CSF (rG-CSF) is routinely used in the prevention of chemotherapy-induced neutropenia and in the setting of bone marrow transplantation. Chronic idiopathic and congenital neutropenic disorders also show improvement after rG-CSF injections. Applications of either rG-CSF or G-CSF gene transfected cells into mice give rise to leukocytosis, which can be measured easily. This makes G-CSF a versatile tool for studying systemic effects of therapeutic proteins delivered by genetically modified cells in vivo. Although the biological activity of G-CSF is not species-specific, studies on long-term expression would require the use of species-identical proteins in order to avoid host immune reactions against the foreign gene product. Because of the physiological and immunological similarity of pigs and human, the pig has become an important large-animal model for biomedical research. We have therefore cloned porcine G-CSF cDNA from RNA isolated from pig PBLs. Pig G-CSF is a 195-amino-acid polypeptide that shares a high degree of homology to human (78%), murine (71%) as well as rat (68%) G-CSF. In contrast to human and murine, but not to rat G-CSF, a different ATG translation start codon is used, resulting in a shorter, but still functional signal sequence.
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PMID:Cloning and sequence analysis of the immediate promoter region and cDNA of porcine granulocyte colony-stimulating factor. 933 86

Hematological and clinical data of 14 children with neuroblastoma treated according to the German neuroblastoma therapy study NB 90 were analyzed. Therapy included 4 or 8 intensive therapy elements N1 (Etoposide 125 mg/m2 day 1-4, Vindesine 3 mg/m2 day 1, Cisplatin 40 mg/m2 day 1-4) and N2 (Vincristine 1.5 mg/m2 day 1 + 8, Dacarbazine 200 mg/m2 day 1-5, Ifosfamide 1500 mg/ m2 day 1-5, Doxorubicin 30 mg/m2 day 6 + 7) in alternating order. The hematological recovery was studied after 86 therapy elements N1/N2. G-CSF had been given in 23 therapy courses, while no cytokine was administered in 63 therapy courses. Mobilization of CD34+ cells was studied in 13 therapy courses with G-CSF. Severe myelosuppression with an absolute neutrophil count < 500/microL was noted 2-4 weeks after each therapy element. The use of G-CSF did not prevent, but shortened neutropenia. There was no difference in the number of infections nor time delay of therapy between the courses with or without G-CSF. In 11 therapy courses G-CSF was started on the day following the last chemotherapy dose (N1: day 5; N2: day 9). In 12 therapy courses G-CSF was given delayed, starting day 12 after the initiation of therapy. Kinetics of granulocyte recovery was similar in the early or delayed application of G-CSF. Neutrophil recovery after the therapy element N1 was earlier and faster compared to that of therapy element N2. The more rapid rise of the neutrophils after the N1 element was accompanied by an effective mobilization of CD34+ cells. Taking into account the limitations of this retrospective study, the data may help to optimize the application of G-CSF in a very intensive therapy study like NB90.
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PMID:[Kinetics of myelopoietic regeneration and mobilization of CD34-positive cells within the scope of the NB90 Neuroblastoma Therapy Study]. 934 Apr 28

A major potential application for ex vivo culture of hematopoietic progenitor cells is the treatment of cytopenia following high-dose chemotherapy and hematopoietic transplantation. We have previously postulated that infusion of a sufficient number of neutrophil postprogenitor cells generated by ex vivo culture of CD34+ cells may be able to abrogate neutropenia. In this article, we describe further development of an efficient stromal-free, cytokine-dependent, static culture system for generation of these cells. Our previous studies indicated that maximal production of nucleated cells and myeloid progenitor cells from PB CD34+ cells occurred with multiple hematopoietic growth factor (HGF), notably the 6-HGF combination of interleukin (IL)-1, IL-3, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and stem cell factor (SCF). In the present study, we determine the contribution of each of these 6 HGF in generation of neutrophilic precursors. SCF, G-CSF, and IL-3 were found to be the most important HGF for production of neutrophilic cells. The 4-HGF combination of IL-3, IL-6, G-CSF, and SCF was optimized by performing dose-response experiments and shown to be as potent as 6 HGF for production of nascent CFU-GM and neutrophilic precursors.
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PMID:Ex vivo culture of peripheral blood CD34+ cells: effects of hematopoietic growth factors on production of neutrophilic precursors. 936 84

This paper reviews the recent studies of interleukin-11 gene expression and regulation, receptor and signal transduction, pharmacologic effects, and preclinical and clinical studies. Interleukin-11 is expressed in cells of mesenchymal origin and gene expression can be modulated by several inflammatory cytokines and agonists. The signaling pathways involved in cytokine induction of interleukin-11 gene expression vary between cell types. In vitro and in vivo studies reveal that interleukin-11 displays a wide spectrum of bioactivities including responses in hematopoietic and nonhematopoietic cells. Preclinical studies in animal models suggest that interleukin-11 may be useful in acceleration of the recoveries of both hematopoietic cells and gastrointestinal mucosal cells after cytoablative therapies. Several clinical studies have demonstrated interleukin-11 to be well tolerated and suggest interleukin-11 is a promising cytokine to prevent both neutropenia and thrombocytopenia in patients with cancer who are receiving chemotherapy.
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PMID:Update on development of interleukin-11. 937 93

The cloning of the gene for the endogenous c-mpl ligand, also known as thrombopoietin, was first reported less than 2 years ago. Recombinant mpl ligands based on this gene have been extensively evaluated in preclinical studies and are now in the early stages of clinical development. In vivo studies have confirmed that c-mpl ligand is a lineage-dominant cytokine and is the primary physiologic regulator of megakaryocytopoiesis. Recombinant mpl ligands can substantially reduce the severity and duration of thrombocytopenia due to myelosuppressive irradiation, chemotherapy, or both. Moreover, when recombinant mpl ligand is used in combination with r-metHuG-CSF, both thrombocytopenia and neutropenia can be prevented to the same degree as with either cytokine alone. In normal animals, the platelets produced in response to recombinant mpl ligand function appropriately and should not pose an undue risk for thrombosis when administered to thrombocytopenic patients. Initial clinical data confirm the safety and biologic activity of these new agents in humans. Clinical development will likely target the most myelosuppressive regimens, including those used in hematopoietic cell transplantation and acute myelocytic leukemia. Ultimately, the clinical benefit of these drugs will likely be judged on their ability to reduce the duration of severe thrombocytopenia and the need for platelet transfusions.
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PMID:Preclinical studies and potential clinical applications of c-mpl ligand. 937 76


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