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Biomedical subjects

J W Adamson

Publications and source records attributed to J W Adamson.

At least 73 records · Page 4Linked to original sources
PubMed1990

The use of recombinant human erythropoietin (rHuEpo) in humans.

Recombinant human erythropoietin (rHuEpo) has now been in clinical trials for over four years. rHuEpo has been shown to be nearly uniformly effective in correcting the anaemia of patients on haemodialysis or patients with progressive chronic renal failure not yet on dialysis. rHuEpo has been shown to be effective in increasing the ability of individuals to donate blood for self-use and to increase the haematocrit in patients with rheumatoid arthritis. Preliminary results indicate that rHuEpo will decrease transfusion requirements of patients with the acquired immune deficiency syndrome who are anaemic. Trials in patients with anaemia associated with cancer or myelodysplastic syndromes are in early stages. rHuEpo will have a major impact as a therapeutic agent, particularly in patients with renal disease.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Treatment of the anemia of progressive renal failure with recombinant human erythropoietin.

To examine the effects of erythropoietin on the anemia of chronic renal disease and on the rate of renal deterioration, we administered recombinant human erythropoietin to 17 patients with anemia and progressive renal failure who did not yet require dialysis (serum creatinine level, 353 to 972 mumol per liter [4.0 to 11.0 mg per deciliter]). The dose of erythropoietin (50 to 150 units per kilogram of body weight) was adjusted according to the hematocrit response. In all 17 patients the anemia responded to erythropoietin. The median hematocrit increased from 0.27 to 0.37. The rate of the response depended on the initial erythropoietin dose and was similar to that observed in patients who were on dialysis. Hypertension was present in 14 patients before therapy, developed during therapy in 2 of the normotensive patients, and worsened in 9 patients, who required additional antihypertensive medications. The rate of the decline in renal function, as measured by serial determination of the reciprocal of the serum creatinine level, did not change significantly as the hematocrit rose (P = 0.78 by the paired t-test) during erythropoietin therapy. All the patients reported improvements in appetite, activity level, and sense of well-being. We conclude that erythropoietin therapy is effective in correcting the anemia of patients with progressive renal failure without affecting renal function, although it may be associated with an increase in blood pressure.

Adult↗
PubMed1989

The growth of Rauscher erythroleukemia cells is mediated by autocrine production of a factor with biological activity similar to interleukin-3.

Under serum-deprived and chemically defined culture conditions, the growth of Rauscher erythroleukemia cells is mediated by an autocrine mechanism. The growth-promoting activity is produced by fresh or irradiated cells and resembles the activity of interleukin-3 (IL-3) in its ability to sustain colony formation from three of four IL-3-dependent cell lines and to induce formation of granulocyte/macrophage (GM) colonies and, in the presence of erythropoietin (Ep), of erythroid bursts and mixed erythroid colonies. IL-3, IL-1, IL-4, IL-6, GM colony-stimulating factor (GM-CSF), G-CSF, M-CSF, Ep, and media conditioned by concanavalin A-stimulated mouse spleen cells or phytohemagglutinin-stimulated LBRM 33 cells were unable to induce proliferation of the Rauscher erythroleukemia cells. Northern analysis of total and polyA-selected RNA extracted from untreated Rauscher cells or from cells 24 hours after irradiation showed the presence of message for M-CSF but not for IL-3, IL-1, GM-CSF, or G-CSF. The production of IL-6 was excluded by a sensitive bioassay. These results indicate that the autocrine growth of the Rauscher cell line is mediated by a growth factor different from IL-3, but with similar biological activity. Activation of the expression of such a growth factor during viral infection may contribute to the generation of leukemic cells that have the property to grow in vitro and generate Rauscher erythroleukemia cell lines.

Animals↗
PubMed1989

Selection of lineage-restricted cell lines immortalized at different stages of hematopoietic differentiation from the murine cell line 32D.

Erythropoietin (Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor- (G-CSF) dependent cell lines have been derived from the murine hematopoietic cell line 32D with a selection strategy involving the culture of the cells in FBS-deprived medium supplemented only with pure recombinant Epo, GM-CSF, or G-CSF. The cells retain the diploid karyotype of the original 32D clone, do not grow in the absence of exogenous growth factor, and do not induce tumors when injected into syngeneic recipients. The morphology of the Epo-dependent cell lines (32D Epo1, -2, and -3) was heterogeneous and evolved with passage. The percent of differentiated cells also was a function of the cell line investigated. Benzidine-positive cells ranged from 1-2% (32D Epo3) to 50-60% (32D Epo1). These erythroid cells expressed carbonic anhydrase I and/or globin mRNA but not carbonic anhydrase II. The GM-CSF- and G-CSF-dependent cell lines had predominantly the morphology of undifferentiated myeloblasts or metamyelocytes, respectively. The GM-CSF-dependent cell lines were sensitive to either GM-CSF or interleukin-3 (IL-3) but did not respond to G-CSF. The G-CSF-dependent cell lines grew to a limited extent in IL-3 but did not respond to GM-CSF. These results indicate that the cell line 32D, originally described as predominantly a basophil/mast cell line, has retained the capacity to give rise to cells which proliferate and differentiate in response to Epo, GM-CSF, and/or G-CSF. These cells represent the first nontransformed cell lines which can be maintained in growth factors other than IL-3 and which differentiate in the presence of physiologic signals. As such, they may represent a model to study the molecular mechanisms underlying the process of hematopoietic differentiation, as well as sensitive targets for bioassays of specific growth factors.

Animals↗
PubMed1989

Regulation of differentiation of murine progenitor cells derived from blast cell colonies under serum-deprived conditions.

We have examined the effect of interleukin 3 (IL-3), granulocyte-macrophage (GM)-, granulocyte (G)-, and macrophage (M)-colony-stimulating factors (CSFs) on the induction of GM colonies from highly enriched murine hematopoietic progenitor cells under serum-deprived conditions. Each growth factor was tested alone or in combination with suboptimal concentrations of the others. The effect of each CSF on GM colony growth in fetal bovine serum (FBS)-supplemented cultures of unfractionated marrow cells is reported for comparison. GM-CSF induced GM colony growth in serum-deprived cultures of purified progenitor cells to the same extent as in FBS-supplemented cultures of unfractionated marrow cells. In contrast, IL-3 was only one-tenth as active in promoting the growth of enriched progenitor cells under serum-deprived conditions when compared with its effect on colony growth from unfractionated marrow. M-CSF and G-CSF were almost completely ineffective in both cases. G-CSF induction of GM colony growth from purified progenitor cells was restored by addition of suboptimal concentrations of IL-3 or GM-CSF, suggesting that either IL-3 or GM-CSF is required to observe the effect of G-CSF. Addition of G-CSF to GM-CSF-stimulated cultures did not increase the maximal number of colonies detected, indicating that these two growth factors may act on the same subset of progenitor cells. Addition of GM-CSF or IL-3 to IL-3- or GM-CSF-stimulated cultures, respectively, increased by 40% the maximal number of colonies detected, suggesting that these two factors act on at least partially separate subsets of GM progenitors. These data parallel the recent observations on the control of human GM colony formation under FBS-deprived conditions and support a model for the control of myeloid differentiation that requires the interplay of different growth factors.

Animals↗
PubMed1989

Effect of red cell hypertransfusion on thrombocytopoietic regeneration following irradiation and bone marrow transplantation in the mouse.

To examine the influence of suppressed erythropoiesis on platelet recovery following marrow injury, C57B1/6 mice were given red cell transfusion or Ringer's citrate. Twenty-four hours later, the animals were given either lethal (9 Gy) irradiation followed by syngeneic marrow or sublethal (3.5 Gy) irradiation and allowed to recover. The adequacy of erythroid suppression was shown by a marked decline in erythroid colony-forming cells (CFU-E) in both marrow and spleen. In both irradiation groups, platelet counts were lower in the hypertransfused mice when compared to nontransfused controls. This decrease in platelet count was observed irrespective of the degree of polycythemia or the time of observation. To determine whether red cell hypertransfusion also affects megakaryocytopoiesis, megakaryocyte colony-forming cells (CFU-MK), megakaryocyte numbers in femoral marrow sections, and megakaryocyte volumes were measured. An increase in CFU-MK-derived colonies was observed in the marrows of hypertransfused animals in both irradiation groups, and in the spleen in the group which received 3.5 Gy. Megakaryocyte numbers and volumes in femoral marrow sections were increased in the hypertransfused mice given 3.5 Gy, but not in the group given 9 Gy. The data show that despite complex effects on megakaryocytes and their progenitors, red cell hypertransfusion delays rather than enhances platelet recovery.

Animals↗
PubMed1989

The promise of recombinant human erythropoietin.

Clinical trials have clearly demonstrated the efficacy of recombinant human erythropoietin (r-HuEPO) (EPOGEN [epoetin alfa]; AMGEN Inc, Thousand Oaks, CA) in the treatment of the anemia associated with end-stage renal disease (ESRD). Nearly all dialysis patients treated with r-HuEPO have responded by reaching target hematocrit levels within 8 to 12 weeks. Maintenance therapy has been effective, and some patients have had stable blood counts for greater than 2 years. The drug has been well tolerated, has resulted in elimination of transfusion dependency, and has evoked no antibody formation. Significant management issues include maintenance of sufficient iron stores to sustain red cell production and the control of blood pressure (BP) elevation associated with increased peripheral vascular resistance resulting from rising hematocrit (HCT) levels. Preliminary results of quality-of-life assessments confirm the beneficial effects of r-HuEPO therapy. This drug should become standard therapy for patients with the anemia of ESRD.

Clinical Trials as Topic↗
PubMed1989

Guidelines for recombinant human erythropoietin therapy.

Extensive testing has proven that recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) corrects the anemia of end-stage renal disease and eliminates the need for transfusions in virtually all patients. Patients whose hematocrit levels are less than 0.30 or who are transfusion dependent are candidates for therapy. A dosage of 50 to 150 U/kg body weight intravenously three times a week produces an increase in hematocrit by approximately 0.01 to 0.02 per week. Once the hematocrit reaches 0.30 the dose is adjusted so that a target hematocrit of 0.32 to 0.38 is maintained. Eighty percent of patients need maintenance doses of r-HuEPO of less than or equal to 150 U/kg; the other 20% of patients require larger doses. Reasons for poor responses include iron deficiency, inflammation due to surgery or infection, and osteitis fibrosa. Most patients require iron supplementation to prevent functional iron deficiency. BP increased in one third of patients, and in 3% seizures occurred during the initial phase of therapy, often associated with a sudden increase in BP. This hypertension can be controlled with medication. Increased dialyzer clotting may occur, which is prevented when heparin doses are adjusted, and dialyzer solute clearances may decrease slightly. Treatment with r-HuEPO does not elicit an antibody response. The mechanism of action of r-HuEPO is identical to that of natural erythropoietin, and therefore is an appropriate therapy for the long-term management of anemia in chronic renal failure.

Anemia↗
PubMed1988

Tumor necrosis factor-alpha and tumor necrosis factor-beta (lymphotoxin) stimulate the production of granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in vivo.

A number of cell types have been shown to elaborate hematopoietic growth factors in response to inflammatory mediators in vitro. To determine if this response occurs in vivo, we have administered levels of TNF-alpha and TNF-beta (lymphotoxin) found during an inflammatory reaction to mice. Using Northern blot analysis to detect tissue levels of hematopoietic growth factor-specific transcripts, and specific biologic and immunologic assays to detect the presence of colony-stimulating factors in the serum, we have found that TNF-alpha and TNF-beta induce the transcription and production of granulocyte-macrophage-CSF, macrophage-CSF, and IL-1. These findings provide an in vivo mechanism for the hematopoietic response to inflammation.

Animals↗
PubMed1988

Erythropoietin: in vitro and in vivo studies of the regulation of erythropoiesis.

The application of recombinant DNA technology to the field of hematology has contributed greatly to our understanding of Erythropoietin (Epo) gene structure and regulation, cellular expression and regulation of hormone production, pharmacokinetics, receptor biology and, ultimately, the value of this hormone as a therapeutic. Areas which will undoubtedly prove fruitful for future research include the mechanisms by which hypoxia influences gene expression, structure/function relationships of the Epo molecule, isolation and cloning of the gene for the Epo receptor, mechanisms of transmembrane signalling and nuclear activation, and the further application of recombinant human Epo in the treatment of other human diseases. Epo is but one example of the contribution that modern biology has made to the understanding of hematopoietic regulation and to the availability of these growth factors for clinical trial.

Anemia↗