摘要:

AbstractThe introduction of hematopoietic growth factors during the past five years has changed the scenery of antitumor treatment. Growth factors following high‐dose chemotherapy or bone marrow transplantation have become established as part of many treatment protocols. The main benefits are earlier recovery of neutrophils resulting in fewer days with fever, antibiotics and hospitalization. Growth factors were found to reduce the treatment‐related morbidity and to improve the practicability of therapeutic regimens. First studies on a prospective chemotherapy dose intensification supported by growth factors are underway. As a further effect of growth factors, an attempted enhancement of antitumor cytotoxicity by recruitment of tumor cells to chemosensitivity or by modulation of antitumor drug metabolism appears realistic based on first data on growth factor priming in AML. New ways to support high‐intensity and myeloablative antitumor strategies are opened by the autologous transplantation of peripheral blood progenitor cells mobilized by growth factors and also by the use of new factors like SCF and the synergistic combination of growth factors as part of future strategies against malignant diso

ISSN:1066-5099    

DOI:10.1002/stem.5530120301

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractGranulcoyte‐macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐3 (IL‐3) are functionally related hematopoietins with overlapping but distinct hematopoietic effects. GM‐CSF supports more myeloid progenitor cells, whereas IL‐3 promotes more erythroid, megakaryocytic and multipotential progenitor cells. Their complementary in vivo biological effects and cross competition for receptor binding prompted the development of PIXY321, a synthetic hybrid protein of GM‐CSF and IL‐3. PIXY321 binds to cell lines expressing specific receptors for either lig‐and, and it exhibits enhanced biological activity in human hematopoietic progenitor cell assays. In preclinical studies, PIXY321 has been shown to accelerate both neutrophil and platelet recovery in rhesus monkeys subjected to sublethal irradiation. Based on these preclinical observations, clinical trials have been initiated examining the therapeutic potential of this agent in ameliorating treatment‐ or disease‐related hematopoietic suppression. The early results indicate that PIXY321 can stimulate multilineage hematopoiesis in vivo and enhance neutrophil and platelet recovery following chemotherapy and bone marrow transplantation (BMT). These results suggest that PIXY321 elicits the biological effects of both its component cytokines and represents a novel means of delivering two independent but interactive c

ISSN:1066-5099    

DOI:10.1002/stem.5530120302

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractInterleukin 6 (IL‐6) and related cytokines, such as leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and IL‐11 exhibit multiple functions and redundancy in biological activities and play important roles in the immune response, hematopoiesis, the nervous system and acute phase reactions. These IL‐6 family cytokines exhibit a similar helical structure, and their receptors are structurally similar and constitute a cytokine receptor super family. In addition, a receptor subunit is shared among these IL‐6 related cytokine subfamily receptors, contributing to one of the mechanisms of functional redundancy of cytokine activities and suggesting the presence of a common signal transduction pathway among these receptors. In this review, we describe the structure of the receptors for IL‐6 and its related cytokine subfamily members. Furthermore, we propose a novel mechanism for the generation of cytokine diversity, i.e. the complex of a cytokine and one of its receptor subunits act as a novel cytokine on the cells that express the other receptor subunit(s) capable of acting as a receptor for the complex. Finally, we describe a Ras‐independent novel signal transduction pathway that utilizes Jak tyrosine kinase family, Stat protein family and yet unidentified H‐7‐sensitive pathway. This signal transduction pathway is commonly generated through the receptors for a wide range of cytokines and

ISSN:1066-5099    

DOI:10.1002/stem.5530120303

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractDuring antigen driven immune responses, antigen‐specific naive B lymphocytes undergo a cascade of events including activation, expansion, mutations, isotype switch, selections and differentiation into either antibody secreting plasma cells or memory B cells. These antigen‐dependent events, which we propose to call immunopoiesis, occur in different areas of secondary lymphoid organs, as well as other nonlymphoid organs. B cells interact with antigens and numerous cell types (T cells, dendritic cells, follicular dendritic cells and macrophages) through numerous cell surface molecules and cytokines. B cells costimulated through their antigen receptor and cytokines such as interleukin 2 (IL‐2), IL‐4 and IL‐10 undergo limited proliferation and differentiation into immunoglobulin (Ig) secreting cells. In contrast, crosslinking of the B cell CD40 antigen, a member of the tumor necrosis factor (TNF) receptor family, results in major cellular activation further modulated by cytokines. In particular, IL‐4 and IL‐13 permit establishment of long‐term factor‐dependent B cell lines, as well as isotype switch towards the production of IgE and IgG4.Addition of IL‐10 to CD40‐activated B cells results in limited proliferation and remarkable differentiation into plasma cells. IL‐10 also participates in isotype switch towards IgG1, IgG3and IgA. The ligand for CD40, a member of the TNF family, is transiently expressed on activated T cells, and interrupted CD40/CD40‐L interactions result in profoundly altered

ISSN:1066-5099    

DOI:10.1002/stem.5530120304

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractIron is a double‐edged sword. In moderate quantities and leashed to protein, it is an essential element in all cell metabolism and growth, but it is toxic when unleashed [1]. Because of its ability to switch back and forth between ferrous and ferric oxidation states, iron is both a strong biological oxidant and reductant.The human diet contains a multitude of natural chemicals which are carcinogens and anti‐carcinogens, many of which act by generating oxygen radicals, which initiate degenerative processes related to cancer, heart disease and aging (the “oxygen radical hypothesis of aging”) [2]. Among these many dietary chemicals are many redox agents, including vitamin C and beta carotene [3].Free radical damage is produced primarily by the hydroxyl radical (·OH) [4, 5]. Most of the ·OH generated in vivo comes from iron‐dependent reduction of H2O2[4, 5]. Supporting too much iron as a free radical‐generating culprit in the risk of cancer, NHANES I data indicated that high body iron stores, manifested by increased transferrin saturation, are associated with an increased cancer risk [6]. Other data [1] shows an increased hear

ISSN:1066-5099    

DOI:10.1002/stem.5530120305

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractWe describe an assay that makes possible the observation of granulomonocytic colonies grown on allogeneic stromal layers and the quantification of the stroma‐adherent colony‐forming cells (CFC). Stromal layers were generated from Stro‐1 positive cells isolated from adherent layers of primary long‐term marrow cultures using magnetic beads coated with the Stro‐1 antibody. The stromal layers consisted mainly of myofibroblastic cells. Marrow fractions depleted of cells bearing receptors for soybean agglutinin (SBA) and enriched in CD34+cells were obtained by panning. SBA‐, CD34+marrow cells were seeded onto stromal cells grown in 96‐well plates. After four weeks, a mixture of cytokines was added (granulocyte‐macrophage colony‐stimulating factor [GM‐CSF]: 25 U/ml, interleukin [IL]‐3: 4 ng/ml, Steel factor: 5 ng/ml and growth factors provided by 3% conditioned medium from the 5637 cell line). Wells with large colonies (containing 103to 104cells) were scored after 14 days. Limiting dilution analysis of data revealed a Poisson distribution of the stroma‐adherent CFC. There was an average of one stroma‐adherent CFC per 167 CD34+enriched marrow cells, which gave an estimated frequency of one CFC per 105unfractionated bone marrow cells. Colonies contained cells that gave rise to CFU‐GM after replating in agar (5–40 CFU‐GM were provided per each stroma‐adherent CFC), but not cells with self‐renewal ability (as indicated by negative results after replating single colonies onto secondary adherent layers). Colonies usually formed from a cobblestone‐area and developed in intimate contact with αSM actin positive stromal cells. Some of the stromal cells were located above granulocytic cells, corresponding to the description of “blanket cells.” This assay should allow the study of colony‐formation on marrow str

ISSN:1066-5099    

DOI:10.1002/stem.5530120306

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractIn this report we examined the expression of several adhesion molecules on human hematopoietic progenitor cells at different maturational stages. Human hematopoietic progenitor cell‐enriched fractions were prepared from bone marrow cells by depleting lymphocytes and monocytes (CD2++, CD14+and CD19+cells). These cells were separated into adhesion molecule‐positive and ‐negative cell populations by immunomagnetic separation methods and then assessed for their ability to form various colony forming cells (CFC). CD44 and CD49d were expressed on multipotent hematopoietic progenitor cells, or mixed colony forming units (CFU‐Mix), erythroid burst forming units (BFU‐E), granulocyte‐macrophage CFU (CFU‐GM) and erythroid CFU (CFU‐E). Leu8 was expressed on CFU‐Mix, BFU‐E and some populations of CFU‐GM, but not CFU‐E. CD11a was expressed on some populations of CFU‐Mix, CFU‐GM and BFU‐E. CD54 was expressed only on some populations of CFU‐GM. These results suggest that Leu8, CD44, CD49d and CD11a appear to play important roles in the differentiation and proliferation of human hematopoietic progenitor cells at different maturational stages in t

ISSN:1066-5099    

DOI:10.1002/stem.5530120307

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe aim of this work was to study the evolution of neutrophil functions in non‐neutropenic cancer patients. Thirty non‐neutropenic patients, median age 35 years (range 19–52), with solid tumors (n = 21) or lymphomas (n = 9) entered a phase I study of five days of s.c. (n = 24) or i.v. bolus (n = 6) lenograstim, recombinant human glycosylated granulocyte colony‐stimulating factor (rHuG‐CSF Chugai‐Rhǒne‐Poulenc), with dose escalation from 1 to 40 m̈g/kg/day. Neutrophil functions were studied before lenograstim (D1) and 24 h after the last dose (D6). Granulocyte count rose in a significant way, and enzyme release, phagocytosis and bacterial killing were stimulated. All patients had improvement of at least one neutrophil function. Directed migration was depressed, although it was still in the normal range. These findings confirm that lenograstim is a potent activator of neutrophil functions in non‐neutropenic cancer patients and may be useful as an adjunct to conventional anti

ISSN:1066-5099    

DOI:10.1002/stem.5530120308

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractErythropoietin is known to be effective for the treatment of anemia in chronic renal failure, but the efficacy of erythropoietin for anemia in other diseases is not so great. Insulin exerts a growth promoting activity in various kinds of cells. In the present study, the effects of insulin on erythroid progenitors (colony forming units‐erythroid, CFU‐E; and burst forming units‐erythroid, BFU‐E) in human bone marrow were examined at various concentrations of recombinant human erythropoietin (rh‐Epo) to clarify the relationship between erythropoietin and insulin. Human insulin stimulated the formation of CFU‐E and BFU‐E in the presence of three concentrations (0.25, 5, and 100 U/ml) of rh‐Epo. Stimulatory effects of human insulin on CFU‐E and BFU‐E were also observed in the nonphagocytic and nonadherent bone marrow fraction (NP‐NA fraction) and in the NP‐NA and T cell‐depleted fraction at each concentration of rh‐Epo. Human insulin further stimulated the CFU‐E and BFU‐E growth in CD34+separated bone marrow cells. These results indicate that the enhancing effect of human insulin on erythroid progenitors is not mediated through monocytes and macrophages or T cells, suggesting a direct

ISSN:1066-5099    

DOI:10.1002/stem.5530120309

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractAn expression vector encoding the human recombinant fusion protein interleukin 6/interleukin 2 (IL‐6/IL‐2) was constructed. When a flexible linker had been synthesized and ligated with the IL‐2 gene fragment by polymerase chain reaction (PCR) amplification, the IL‐6 gene fragment was unidirectionally inserted into the upstream of the linker‐IL‐2 sequence. The molecule of the IL‐6‐linker‐IL‐2 fusion gene namedE. coliDH5α/pfIL‐6/2 was cloned and identified by DNA sequencing. The expressed protein named as CH925 showed a strong band on SDS‐PAGE and amounted to 32% of total cell protein, and its estimated molecular weight was about 37 kDa. The fusion protein purified by gel filtration and reversed‐phase HPLC showed as almost homogeneous. CH925 possesses both IL‐2 and IL‐6 activities when assayed by CTLL2‐ and 7TD1‐dependent cell lines, respectively. The specific activity of IL‐2 was 2.1 x 106U/mg while that of IL‐6 was 2.3 x 108U/mg. Our studies exhibited that CH925 exerted a significant augmentative effect on the growth of erythroid colony forming units (CFU‐E), and synergized with erythropoietin (EPO) and/or IL‐3 in a dose‐dependent way. Our experimental results also showed CH925 at a low dose causing active lymphokine‐activated killer (LAK) cell proliferation more vigorous than IL‐2 and/or IL‐6 (p<0.001). CH925 is a novel fusion protein, being neither IL‐6 nor IL‐2, more potent than IL‐2 and/or IL‐6 and causing non‐IL‐2 and non‐IL‐6 functions of strong EPO‐like and mild IL‐3‐like effects on erythroid progenitor cell gr

ISSN:1066-5099    

DOI:10.1002/stem.5530120310

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY