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Results for “Granulocyte Precursor Cells”

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PubMed2004

A predictive model of human myelotoxicity using five camptothecin derivatives and the in vitro colony-forming unit granulocyte/macrophage assay.

PURPOSE: Many promising anticancer drugs are limited by myelosuppression. It is difficult to evaluate human myelotoxicity before a Phase I study because of the susceptibility of humans and animals to hematotoxicity. The purpose of this study was to establish a reliable method to predict the human maximum tolerated dose (MTD) of five camptothecin derivatives: SN-38, DX-8951f, topotecan, 9-aminocamptothecin, and camptothecin. EXPERIMENTAL DESIGN: The myelotoxicity of SN-38 and DX-8951f were evaluated on bone marrow from mice, dogs, and humans using a 14-day colony-forming unit, granulocyte-macrophage (CFU-GM) assay to determine the 50%, 75%, and 90% inhibitory concentration values (IC50, IC75, and IC90, respectively). RESULTS: Species differences in myelotoxicity were observed for SN-38 and DX-8951f. Using human and murine IC90s for myelotoxicity of these compounds and other camptothecin compounds (topotecan, 9-aminocamptothecin, and camptothecin), in vivo toxicological data, and pharmacokinetic parameters (data referred to in the literature), human MTDs were predicted retrospectively. The mechanism-based prediction model that is proposed uses the in vitro camptothecin assay and in vivo parameters on the basis of free fraction of area under the concentration-curve at the MTD (r2 = 0.887) and suggests that the human MTDs were well predicted for the five camptothecin derivatives by this model rather than by other models. CONCLUSION: The human MTDs of the camptothecin drugs were successfully predicted using the mechanism-based prediction model. The application of this model for in vitro hematotoxicology could play an important role for the development of new anticancer agents.

Animals↗

PubMed1980

Resistance of human bone marrow CFUC to high-dose methotrexate cytotoxicity.

We have studied the susceptibility of human bone marrow cells to the high-dose methotrexate (MTX) cytotoxicity by the in vitro cultures of the granulocyte precursor cells (CFUC) in a medium containing various concentrations of MTX. Cultures of cells were exposed to 10(-9) to 10(-2) M MTX for 2, 6, 24 h and 10 days. About 50% of CFUC were killed by a 10-day exposure to 10(-7) M MTX or more. However, there was no loss of CFUC even at a drug concentration of 10(-3) M MTX if the exposure time was kept for 24 h or less. Within a 2 h exposure time, CFUC was resistant to MTX at the concentration of 10(-2) M. Such a strong resistance of bone marrow cells to MTX may warrant clinical usefulness of the high-dose and short-time MTX therapy with leucovorin rescue, which has widely been used in the treatment of various malignant diseases.

Bone Marrow↗

PubMed1981

Splenic granulocytopoiesis and production of colony-stimulating activity in lymphoma and leukemia.

Spleen cell production of granulocyte-macrophage colony stimulating activity (CSA) and colony forming capacity (CFU-GM) from 59 patients with Hodgkin's and non-Hodgkin's lymphoma, acute (AML) and chronic myeloid leukemia (CML), and control subjects was quantified to evaluate local cellular potential for modulating splenic granulocytopoiesis. Mononuclear spleen cell conditioned media stimulated myeloid CFU-GM by human nonadherent marrow target cells. In contrast to conditioned media produced by marrow and peripheral blood cells, the vast majority of spleen CSA was generated by nonadherent lymphoid cells rather than adherent monocytic cells. The nonadherent cells producing CSA were non-T cells (assessed by sheep erythrocyte rosetting), with 98% +/- 2% CSA produced by the nonrosetted fraction (B lymphocytes and null cells), and had a peak density heavier than that of the adherent spleen CSA-producing cells. Dose response curves demonstrated significantly increased cellular CSA production from patients with lymphomas and AML in remission. In a high proportion of patients, foci of immature granulocytic cells were found by specific cytochemical staining of histologic sections of spleens. A limited degree of splenic granulocytopoiesis was demonstrated morphologically and by CFU-GM incidence. CSA was not detectable in conditioned medium prepared from nonadherent spleen cells from 5 patients with CML, due to a nondialyzable substances(s) produced by the nonadherent cells which inhibited normal CFU-GM response to CSA. The high CFU-GM incidence and extensive leukemic granulocytopoiesis present in the CML spleens suggests diminished effect of this inhibitor on leukemic as opposed to normal granulocytic precursor cell proliferation.

Cell Adhesion↗

PubMed1992

Expression patterns of c-myb and of v-myb induced myeloid-1 (mim-1) gene during the development of the chick embryo.

The v-myb oncogene of the acute avian leukemia virus E26 encodes a transcription factor that directly regulates the promyelocyte-specific mim-1 gene (Ness, S.A., Marknell, A. and Graf, T. Cell, 59, 1115-1125). We have investigated the relationship between the c-myb proto-oncogene and the transcription of the mim-1 gene both in vitro and in vivo. We demonstrate that the c-myb protein can transactivate the transcription of mim-1 in a transient transfection assay. In the chick embryo, we confirm that mim-1 is specifically expressed during granulopoiesis and we show that the expression of c-myb and mim-1 are perfectly correlated in the granulocytic spleen and pancreas. However we suggest that mim-1 is efficiently transcribed in the absence of c-myb in the yolk sac and in the promyelocytes at the onset of the colonization of the bursa of Fabricius. On the other hand c-myb transcripts detected in the early hemopoietic progenitor cells, in lymphoid cells and in proliferative epithelia are never associated with mim-1 transcription. We conclude that the granulocyte-specific mim-1 gene is regulated by c-myb-dependent and c-myb-independent mechanisms depending upon the environment in which granulocytic precursor cells differentiate.

Animals↗

PubMed1980

Granulocyte-macrophage colonies in cultures of human fetal liver cells: morphologic and ultrastructural analysis of proliferation and differentiation.

Fetal liver cells from 6-12-week-old human fetuses were cultured in soft agar to study growth patterns of the granulocyte-macrophage colony forming cells (CFU(c)) and to characterize the cellular components of these colonies by morphologic, cytochemical and ultrastructural methods. Liver cell suspensions prepared from 31 fetuses obtained by vaginal interruptions of pregnancies, were seeded in soft agar over feeder layers of normal human leukocytes. At all gestational ages examined, agar colony numbers ranged from 44 +/- 15 to 89 +/- 44/2 x 10(5) cells seeded. Colony frequencies, size and gross morphology closely resembled those derived from adult human marrow. Morphologic, cytochemical and ultrastructural examinations showed that 92% of the colonies were granulocytic with incomplete maturation, as found in adult human marrow colonies. Density fractionation of the cells produced a low density cellular fraction which gave a 3- to 5-fold improved cloning efficiency. This study shows that human fetal livers of 6-12 weeks gestational age contain CFU(c) comparable to that found in adult marrow in their frequency, size, density and dependence on colony stimulating factor, and which differentiate mainly into mature or immature granulocytes. It is suggested that the lack of granulopoiesis in vivo in the early human fetal liver is probably not related to CFU(c) deficiency or defective differentiation. An alternative explanation involving impaired regulatory mechanism(s) should be sought.

Cell Differentiation↗

PubMed1981

Haemopoietic microenvironments in vitro: ultrastructural aspects.

Haemopoietically active long-term bone marrow cultures from several species have been investigated ultrastructurally. Human, tree shrew and mouse cultures generally support granulopoiesis, although recently it has been possible to convert a granulopoietic mouse culture to extensive erythropoiesis. The haemopoietic products of the cultures include granulocytes (neutrophil and basophil), mast cells, monocytes, megakaryocytes and all stages of the erythrocytic series. Plasmacytes and occasional lymphocytes have been observed in small numbers in human cultures (possible indicating retention rather than formation). The stromal elements of the adherent layer of these cultures include endothelial cells, reticulum cells, fat cells and fibroblasts. The adherent layers are responsible for the inductive microenvironment within the cultures, and show features specific for the line of differentiation. In the granulocytic cultures there is close association between developing fat cells (reticulum cells) and granulocyte precursors. Endothelial cell monolayers cover large regions of these cultures, and the areas beneath this monolayer are rich in early granulocytes. Mature granulocytes and monocytes migrate through the endothelial layer, demonstrating in vitro "transmural passage". Cultures stimulated for erythropoiesis show a considerable reduction in fat cells, in endothelial cell cover and in the numbers of classical monocytes. Erythropoiesis appears to be promoted by a close association of the entire erythrocytic series with monocytic cells, forming "erythroblastic islets" in vitro. A possible pathway of intracellular communication between differentiating haemopoietic cells and the stromal cells in their microenvironment is suggested.

Adipose Tissue↗

PubMed2003

Response of hematopoiesis to cyclophosphamide follows highly specific patterns in bone marrow and spleen.

Sublethal cyclophosphamide treatment induces unique regeneration patterns in bone marrow and the spleen of a mouse. Colony-forming units spleen (CFU-S)(day 8), CFU-granulocyte-macrophage (GM), nucleated cell counts, and their differentials in bone marrow, spleen, and peripheral blood were determined in mice treated with a single dose of cyclophosphamide. To study further the mechanisms underlying the unique patterns of hematopoietic regeneration after cyclophosphamide, mRNA levels for stem cell factor (SCF), Flt-3 ligand, and macrophage inflammatory factor (MIP)-1 alpha cytokines were determined in bone marrow and spleen. Granulocyte precursor cells were less depleted by cyclophosphamide compared to erythroid nucleated cells and lymphocytes both in bone marrow and spleen. Rapid expansion of granulopoietic cells increased the granulocytic/erythroid ratio significantly during regeneration. CFU-S in the bone marrow and the spleen showed different sensitivity in vivo but not in vitro to cyclophosphamide; CFU-GM were equisensitive in both sites. In bone marrow, an initial fast recovery of CFU-S and CFU-GM on days 2 to 3 was followed by a secondary deep decline in their numbers occurring between days 5 and 7. This decline was accompanied with a depression of CFU-S proliferation and with significantly increased CFU-S numbers in the peripheral blood. In the spleen, absolute CFU-S and CFU-GM numbers were increased several-fold at this time. Seven days after cyclophosphamide, the spleen contained 69% of the total body CFU-S compared to 4% in controls. Splenectomy did not abolish the secondary disease of CFU-S in the bone marrow, but it led to a marked elevation of circulating leukocytes and CFU-S. There was an eight-fold increase in the SCF mRNA level in the bone marrow 2 days after cyclophosphamide, corresponding with a high proliferation rate of CFU-S. No significant changes in mRNAs for Flt-3 ligand and MIP-1 alpha have been found. This in-depth analysis of murine hematopoietic responses to cyclophosphamide provides evidence for the complexity of the involved local and systemic regulations. This represents a significant challenge to experimental hematology, which could now be tackled with methods allowing the study of changes in the gene expression during cyclophosphamide-induced hematopoietic damage.

Aldehyde Dehydrogenase↗

PubMed1990

Histiocytic necrotizing lymphadenitis or Kikuchi's disease. Anatomo-clinical study of 4 cases.

Histiocytic necrotizing lymphadentis (HNL) is an uncommon clinical and histologic entity, essentially diagnosed in Japan since 1972. The clinical picture is usually characterized by cervical lymphadenopathy and fever, females being more often affected. Leukopenia and elevated erythrocyte sedimentation rate are frequent. The etiology is still unknown, but a viral origin is most likely. The clinical course is always favorable without treatment, except in one case. The histological picture, with necrotic foci surrounded by histiocytes, immunoblasts, small T lymphocytes and plasmacytoid monocytes (so-called plasmacytoid T cells), is characteristic. Nevertheless, HNL may be mistaken for malignant lymphoma both clinically and histologically. We report 4 cases of HNL. One of these presented severe leukothrombopenia; the serum of this patient significantly suppressed the maturation of granulocytic precursor cells in the bone marrow.

Adolescent↗

PubMed1979

Antibody-dependent cellular cytotoxicity against tumor cells. I. Cultivated bone marrow-derived macrophages kill tumor targets.

Mouse bone marrow cells are cultivated in a liquid culture system in the presence of fibroblast conditioned medium. Under these conditions, proliferation of macrophage and granulocyte precursor cells is induced. Cells of a 5-day-old culture are shown to act as cytotoxic effector cells against tumor targets such as P815, E14, YAC and L5178Y. The effector cell is of macrophage origin since it is susceptible to treatment with the alloantiserum Mph-1.2 plus complement. The kinetics of the reaction resembles the kinetics for killer (K) lymphocyte lysis. In contrast to bone marrow cells, peritoneal macrophages do not show cytotoxic activity against antibody-coated tumor targets although they are susceptible to activation to cytotoxicity by lymphokines. The possible relationship of bone marrow effector cells and K lymphocytes is discussed.

Animals↗

PubMed1991

Granulocytic sarcoma presenting as an epidural mass with acute paraparesis in an aleukemic patient.

Granulocytic sarcomas are rare tumors composed of granulocytic precursor cells. They are most commonly encountered in patients with acute myelogenous leukemias and myeloproliferative disorders in blast crisis. Rarely, patients presenting with granulocytic sarcoma show no evidence of acute leukemia. The authors report an aleukemic patient with acute paraparesis from an epidural granulocytic sarcoma. Only five such cases have been reported previously. Immunoperoxidase stain for lysozyme and chloroacetate esterase stain were used to prove the myeloid origin of the tumor cells.

Aged↗

PubMed1997

Granulocytic differentiation of HL-60 cells results in spontaneous apoptosis mediated by increased caspase expression.

HL-60 cells differentiating into neutrophil-like cells die an apoptotic death in vitro. Susceptibility to apoptosis is associated with decreased Bcl-2 protein and mRNA expression; however, the effect of differentiation on the expression of pro-apoptotic caspases is unknown. Spontaneous apoptosis occurred 6 days after retinoic acid treatment. Western blotting showed loss of Bcl-2 by day 7, and new expression of ICE (caspase 1) and CPP32 (caspase 3) protein by day 2. Northern analysis demonstrated loss of Bcl-2 mRNA and increases in ICE mRNA by day 2; CPP32 mRNA was unchanged. Differential Bcl-2 and ICE mRNA expression was also found when granulocytic differentiation was stimulated by DMSO. Differentiated HL-60 cell lysates exhibited functional ICE proteolytic activity. De novo caspase expression was responsible for the development of spontaneous apoptosis, since specific inhibitors of ICE (YVAD-CMK) and CPP32 (DEVD-CHO), inhibited retinoic acid induced spontaneous apoptosis. Functional maturation and susceptibility to apoptosis are both inducible and linked in this granulocyte precursor cell line.

Apoptosis↗

PubMed1975

Characterization of immunoglobulin-bearing and other small lymphocytes in mouse bone marrow by sedimentation and electrophoresis.

125I-antiglobulin binding and radioautography have been used to define the sedimentation and electrophoretic properties of immunoglobulin-bearing and other small lymphocytes in bone marrow. Bone marrow cell suspensions from CBA mice were exposed to 125I-labeled rabbit anti-mouse immunoglobulin for 30 min at 0 degrees C. Cell fractions were collected after either sedimentation at unit gravity or continuous free-buffer film preparative electrophoresis. The sedimentation profiles of labeled, antiglobulin-binding small lymphocytes and of unlabeled small lymphocytes were identical, peaking at 2.6 mm/hr, except for 5% of the labeled small lymphocytes which sedimented at 3.8 to 4.1 mm/hr. In electrophoretic fractions most labeled small lymphocytes were contained in a peak of low mobility and unlabeled small lymphocytes were of intermediate mobility, but high mobility fractions also contained small numbers of labeled and unlabeled small lymphocytes. Small lymphocytes comprised 80 to 85% of all nucleated bone marrow cells in fractions taken at the peak of the small lymphocyte distribution profile after either sedimentation or electrophoresis, accompanied mainly by either erythroid or granulocytic precursor cells, respectively. The results demonstrate that small lymphocytes with readily detectable surface immunoglobulin in the bone marrow closely resemble those in peripheral lymphoid tissues with respect to their sedimentation and electrophoretic properties. The possibility is raised that the rapidly sedimenting immunoglobulin-bearing small lymphocytes in bone marrow are a functionally distinct group of potential precursor cells. Non-antiglobulin-binding small lymphocytes in bone marrow resemble electrophoretically the double negative (immunoglobulin -and theta -negative) small lymphocytes in other lymphoid tissues. Small lymphocytes of high electrophoretic mobility, prominent in the theta- bearing lymphocyte populations of peripheral lymphoid tissues, are few in bone marrow. Lymphocyte-rich suspensions, containing either high or low proportions of immunoglobulin-bearing small lymphocytes, can be separated from bone marrow by electrophoresis

Animals↗

PubMed1978

Trimethoprim and sulphamethoxazole inhibition of haematopoiesis in vitro.

The effect of trimethoprim and sulphamethoxazole on haematopoiesis was studied in vitro using cloning techniques for human and murine erythroid and granulocytic precursor cells. Trimethoprim was found to inhibit granulopoiesis and erythropoiesis in vitro in a dose-dependent fashion with approximately 50% inhibition of human erythroid and granulocytic colonies at a therapeutically achievable concentration of 7 micrograms/ml. Sulphamethoxazole was also shown to impair haematopoiesis in vitro. The inhibition caused by both these constituents of co-trimoxazole was completely reversed by folinic acid. The data suggest that co-trimoxazole can impair human haematopoiesis by inhibition of tetrahydrofolate synthesis. These observations suggest that the clinical haematopoietic toxicity of trimethoprim-sulphamethoxazole can be abrogated by simultaneous administration of folinic acid.

Adult↗

PubMed2004

A short note on the nucleolar size and density in apoptotic leukemic granulocytic precursors (HL-60 cells).

The present study was undertaken to provide more information on the nucleolar size and density in mononuclear blastic granulocytic precursors represented by HL-60 cells the proliferation of which was blocked by photodynamic treatment (PDT) which induced apoptotic process without preceding terminal maturation. Both the nucleolar size and density did not change in apoptotic cells in comparison with controls. Thus, large and dense nucleoli in apoptotic cells are not necessarily related to the nucleolar biosynthetic or cell proliferation activity.

Aminolevulinic Acid↗

PubMed2003

3-Deazauridine triggers dose-dependent apoptosis in myeloid leukemia cells and enhances retinoic acid-induced granulocytic differentiation of HL-60 cells.

Therapeutic nucleoside analogue 3-deazauridine (DU) exerts cytotoxic activity against cancer cells by disruption of DNA synthesis resulting in cell death. The present study evaluates whether DU alone at doses 2.5-15 microM or in combination with all trans retinoic acid (RA) or dibutyryl cAMP (dbcAMP) is effective against myelogenous leukemia. The data of this study indicate that DU induces dose-dependent cell death by apoptosis in myeloid leukemia cell lines HL-60, NB4, HEL and K562 as demonstrated by cell staining or flow cytometry and agarose gel electrophoresis. 24h-treatment with DU produced dose-dependent HL-60 cell growth inhibition and dose-independent S phase arrest that was not reversed upon removal of higher doses of DU (10-15 microM). Exposition to nontoxic dose of DU (2.5 microM) for 24h followed by RA or dbcAMP and 96 h-cotreatment with DU significantly enhanced RA- but not dbcAMP-mediated granulocytic differentiation. Cell maturation was paralleled with an increase in the proportion of cells in G1 or G2+M phase. We conclude that, depending on the dose or the sequence of administration with RA, an inhibitor of DNA replication, DU triggers a process of either differentiation or apoptosis in myeloid leukemia cells.

3-Deazauridine↗

PubMed1996

Advances in bone biology: the osteoclast.

Much has been learned about the cell biology and molecular biology of the osteoclast in the last 5 yr. The osteoclast appears to be derived from CFU-GM, the committed monocyte-granulocyte precursor cell. This cell then differentiates into more committed precursors for the osteoclast. The role of the marrow microenvironment appears to be critical for murine osteoclast formation, although in human systems it appears to be nonessential but acts to enhance osteoclast formation and resorption. The osteoclast has been shown to be a secretory cell capable of producing both stimulators and inhibitors of osteoclast formation and resorption. The identification of the role of protooncogenes, such as c-fos and pp60c-src, in osteoclast differentiation and bone resorption has provided important insights into the regulation of normal osteoclast activity. Studies such as these should help us to dissect the pathophysiology of abnormal osteoclastic activity, such as seen in hypercalcemia of malignancy, osteopetrosis, and Paget's disease of bone. Future research is needed to further delineate the signaling pathways involved in osteoclastic bone resorption in response to cytokines and hormones, as well as to identify the molecular events required for commitment of multipotent precursors to the osteoclast lineage. Development of osteoclast cell lines may be possible and would greatly enhance our understanding of the biology of the osteoclast. Utilization of current model systems to examine the effects of cytokines and hormones on osteoclast precursors in vitro and in vivo and the ability to obtain large numbers of highly purified osteoclasts for production of osteoclast cDNA libraries should lead to important new discoveries in osteoclast biology.

Animals↗

PubMed1997

[G-CSF in radiochemotherapy].

BACKGROUND: G-CSF enhances the division, maturation and release of granulocyte precursor cells. The shortening of chemotherapy-induced leukopenia via G-CSF is well documented in literature, with fractionated radiotherapy alone one finds a distinct increase of the granulocyte level. There are only few results for combined simultaneous radiochemotherapy. PATIENTS AND METHODS: In the Department of Radiotherapy of the University of Erlangen 102 patients were treated with G-CSF since 1992. Twenty-eight patients (31 applications) undergoing radiotherapy only (n = 4) or combined simultaneous radiochemotherapy (n = 27) received G-CSF interventional daily. These results are presented and discussed. Indications for the application of G-CSF were severe leukopenia below 1000/mm3 (level IV according to WHO) or rapid decreasing leukocytes during therapy. G-CSF was not applied during chemotherapy and terminated at least 24 h before the next chemotherapy cycle. r-metHuG-CSF (Filgrastim, Neupogen) was used subcutaneously. Documented were the duration until the leukocyte increase, neutrophil granulocytes, thrombocytes, interruption of radiotherapy, febrile episodes and side effects. RESULTS: In case of severe leukopenia (< 1000/mm3 n = 16) the leukocytes increased after 3 days of G-CSF application, the radiotherapy was interrupted in 2 cases, terminated in 1 case. Four patients had lever before during G-CSF 4 additional febrile episodes occurred. If G-CSF application was started between leukocyte levels of 1000 and 1500/mm3 after 1 day the leukocytes increased in 9 of 10 cases beyond the starting level. Interruption of radiotherapy was not necessary. Only 1 febrile episode occurred (1/11). There were no relevant side effects of G-CSF. CONCLUSIONS: Rapidly developing or severe leukopenia during radio(chemo)therapy are indications for an interventional application of G-CSF. The leukocyte level for the start of G-CSF should be chosen so that without G-CSF an interruption of therapy or a level IV leukopenia seems to be unavoidable.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Selective inhibition of polymorphonuclear neutrophil activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Although the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), via its interaction with the Ah receptor, is an extremely potent carcinogen and immunosuppressive agent in experimental animals, its possible actions on polymorphonuclear (PMN) function have not been determined. In addition to their importance against infectious organisms, PMNs have been implicated in antitumor resistance. The present studies examined the effects of in vivo exposure to TCDD on PMN function in B6C3F1 (TCDD sensitive, presence of high affinity Ah receptor) and DBA/2N (TCDD resistant at low doses, defective Ah receptor) mice. Animals received a single oral exposure of 5 or 10 micrograms/kg of TCDD and PMNs were obtained 5 days later from the peritoneal cavity following elicitation with sodium caseinate. TCDD reduced the cytolytic and cytostatic activity of PMA-activated PMNs in B6C3F1, but not in DBA/2N mice, suggesting that this response segregates with the Ah locus. Furthermore, TCDD was found to bind specifically to PMNs from Ah-responsive mice. Neither the production of superoxide and hydrogen peroxide nor degranulation, the latter measured by beta-glucuronidase release, was impaired. Supernatants recovered from PMN cell cultures of TCDD-sensitive mice, but not from resistant DBA/2N mice, showed reduced killing capacity for actinomycin D-treated L929 tumor cells, while their ability to bind to tumor cells was not altered. These data suggest that TCDD interferes with PMN-mediated tumor cell killing by altering the production or secretion of a cytolytic factor. Examination of bone marrow stem cells revealed that granulocytic but not monocytic colonies were reduced after TCDD exposure in vivo and in vitro. Although mature PMNs had detectable levels of Ah receptor, exposure in vitro of these cells to TCDD had no effect on antitumor activity. Thus, it is possible that TCDD may affect PMNs at the level of hematopoiesis, via a direct interaction with granulocyte precursor cells, or modulate PMNs at different stages of maturation.

Animals↗