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PubMed1983

Effect of mannitol and plasma on the cytotoxicity of cisplatin.

A soft agar cell culture for human granulocyte precursor cells (CFU-c) was used to assess the cytotoxic effect of cisplatin before and after preincubating the drug with either mannitol and/or fresh human plasma. Consistent growth inhibition of CFU-c was found with survival of 87, 64 and 34% at cisplatin concentrations of 10(-7) M, 10(-6) M and 10(-5) M respectively. Dose-related survival was not changed by preincubating cisplatin with mannitol in molar ratios of 1:100 and 1:1000 for 4 and 24 hr. Preincubating 10(-5) M cisplatin with human plasma increased CFU-c survival corresponding to a loss of activity of 92 and 98% after 4- and 24-hr preincubations respectively. No significant difference in survival of CFU-c was noted whether bone marrow cells were exposed to cisplatin in human plasma or in the ultrafiltrate of human plasma. Mannitol did not change the decrease in cisplatin activity due to plasma protein binding. These data indicate that the cytotoxic effect of cisplatin can be reduced by exposure to human plasma but not to mannitol.

Adult↗
PubMedDate not supplied

On the nucleolar size and density in human early granulocytic progenitors, myeloblasts.

Human myeloblasts were studied in bone marrow of patients suffering from chronic phase of chronic myeloid leukaemia to provide more information on the nucleolar diameter in these early granulocytic progenitors. These cells are a convenient model for such study since the number of myeloblasts in diagnostic bone marrow smears of investigated patients is larger than in not-leukemic persons because of the increased granulopoiesis. The nucleolar diameter was measured in myeloblasts after various cytochemical procedures such as methods for visualisation of RNA, DNA and proteins of AgNORs using digitized images and image processing. The results clearly demonstrated that values of the nucleolar diameter depended on the procedures used for visualising nucleoli. It seems to be also clear that a close relationship exists between the diameter of nucleoli and their number since the larger the number of nucleoli per cell the smaller their mean size. However, one of multiple nucleoli present in the nucleus is usually significantly larger. Moreover, the possibility exists that the variability of nucleolar diameter of leukemic myeloblasts and thus the heterogeneity of these cells might depend on various stages of the cell cycle as supported by nucleolar measurements on aging leukemic myeloblasts (K 562 cells) in vitro. Since the staining density of small and large nucleoli did not differ substantially after staining for RNA, it seems to be likely that the nucleolar size is directly related to the total RNA content in myeloblasts. In addition, karyometry combined with RNA cytochemistry still appears to be an useful tool to study nucleoli at the single cell level.

Cell Nucleolus↗
PubMed1987

[Characteristics of hematopoiesis regeneration in subcutaneous bone implants in aging mice].

Femurs from both young and old mice were implanted subcutaneously to young syngeneic recipients. 2-2.5 months after surgery femoral marrow grafts were repopulated with nucleated cells and macrophage-granulocyte precursor cells irrespective of the donor's age. Marrow depletion of femurs prior to implantation caused a sharp decrease in hemopoietic repopulation of implants from old, but not young, donors. It is concluded that age-dependent functional peculiarities of stromal microenvironment can be visualized owing to the extraordinary local regenerative demand.

Aging↗
PubMed1993

[Granulopoietic inhibitor].

The differentiation and proliferation of granulocytes are specifically supported by G-CSF. On the other hand, little is known about the negative modulation of granulopoiesis. We had found that the sera obtained from patients during the recovery phase of hematopoiesis after chemotherapy inhibited the formation of CFU-G, suggesting the modulation of granulopoiesis by negative regulator(s). As the inhibitory effect was specific for CFU-G, the inhibitor in this inhibitory sera was suggested the soluble G-CSF receptor. Several G-CSF receptor fragments were detected in the concentrated fractionated-urine by the immunoblot analysis using the specific antibody against the cytokine receptor homologous (CRH) domain of G-CSF receptor. G-CSF binding protein was successfully obtained from normal human plasma by G-CSF affinity column. Major component was the 90Kd of protein which was thought to be the extracellular domain of G-CSF receptor by the immunoblot analysis. About 90Kd- and 30Kd- bands of the binding-complex formation between G-CSF monomer and the extracellular domain or the fragment of G-CSF receptor were shown in the immunoblot analysis using anti-G-CSF Ab. CFU-G formation was suppressed by the solution of soluble G-CSF receptor fragments, suggesting the competition of G-CSF which bind to granulocyte precursor cells.

Granulocyte Colony-Stimulating Factor↗
PubMed1982

Effects of GM-CSF deprivation on precursors of granulocytes and macrophages.

Culture of C57BL bone marrow cells in the absence of GM-CSF led to a loss of recoverable granulocyte-macrophage colony-forming cells of 2% per hour. The rate of loss of progenitor cells in cultures of CBA fetal liver cells was 5-6% per hour. Surviving colony-forming cells exhibited a normal responsiveness to GM-CSF but generated smaller colonies than normal when subsequently stimulated by GM-CSF. Transfer of washed individual day-3 granulocyte-macrophage colony cells to cultures lacking GM-CSF indicated that most cells were unable to survive or proliferate in the absence of GM-CSF. Death of transferred cells was rapid and invariable when the cells were from macrophage-forming colonies. However some cells from 40-70% of granulocyte-forming colonies were able to undergo one or two divisions in the absence of GM-CSF. This phenomenon was seen most often with cells from colonies where matching colony cells exhibited a higher-than-average proliferative capacity in parallel stimulated cultures. The results indicate the difficulty that will be encountered in obtaining valid metabolic data from unstimulated populations of granulocyte-macrophage precursor cells. The ability of some granulocyte precursor cells to exhibit limited proliferation following GM-CSF deprivation suggests that significant amounts of GM-CSF may be bound to or be internalized in some precursor cells and result in cell division in the absence of GM-CSF from culture medium.

Animals↗
PubMed2003

Overexpression of RANKL implicates IFN-beta-mediated elimination of B-cell precursors in the osteopetrotic bone of microphthalmic mice.

The microphthalmic (mi) mouse possesses a dominant negative mutation in the microphthalmia-associated transcript factor (MITF) transcription factor. These animals are characterized by reduced numbers of peripheral mast and natural killer (NK) cells, are osteopetrotic because of osteoclast reduction and malfunction, lack functional melanocytes, and are deficient for maturing B-cells within the bone marrow. Granulocyte precursor cells, however, are functionally maintained within the mi bone marrow. A central question has been whether the B-cell deficiency of the mi mouse marrow is caused by the absence of an MITF-controlled gene product or because of the compromised, osteopetrotic environment. In this report, we examined mi marrow by performing transcriptional mapping analyses of candidate genes whose products are instrumental for functional osteoclast and B-cell development. Surprisingly, the expression of a subset of such genes including RANKL, stromal-derived factor (SDF-1), B-cell lymphotactin chemokine (BLC), and RANK was dramatically enhanced in the mi marrow. Normal and mutant marrow were also analyzed by subtractive transcript cloning, which identified a number of known and unknown genes with altered transcriptional activity. One such unknown mouse gene possesses a human counterpart that is interferon-beta (IFN-beta) inducible, suggesting the osteopetrotic marrow is enriched for IFN-beta, a cytokine that is known to eliminate B-cell precursors. A model is proposed suggesting excess RANKL sets off a cascade of cytokine production including IFN-beta that leads to the preferential elimination of B-cell precursors in the marrow of osteopetrotic marrow.

Amino Acid Sequence↗
PubMed1980

Investigations on the pool size, proliferative state and differentiation pattern of splenic CFUC in normal dogs.

In the present study we investigated the absolute numbers of granulocytic progenitor cells (CFUc) in the spleens of adult normal dogs, their differentiation pattern and also their proliferative state. Between 10 and 40 times as many CFUc were found in the spleens of individual dogs as were present in the total blood volume at the same time under physiological conditions. About 16% of the splenic CFUc were in the DNA synthetic phase. In spite of the presence of CFUc in the splenic tissue, there was a lack of morphologically identifiable granulocytic precursor cells and hence no extramedullary granulocyte production. The similarities between circulating CFUc and the splenic CFUc with respect to their differentiation pattern in vitro and their cell cycle state suggest that the CFUc that reside in the splenic tissue are identical to thea CFUc population in the circulation.

Animals↗
PubMed1985

A sensitive method for immunophenotyping stored leukemia and lymphoma cells with preservation of morphological detail.

We describe a method by which density-separated mononuclear preparations of blood and bone marrow may be stored and batch-processed for immunophenotyping by the indirect immunoperoxidase (IP) technique. The method gives excellent preservation of cellular detail thus permitting clear morphological categorization of IP-positive and IP-negative cells. We compared the immunofluorescence (IF) and IP techniques for estimation of the proportions of cells displaying a variety of antigens; with normal blood cells the results were closely similar but with chronic lymphocytic leukemia (CLL) cells, IP was superior to conventional IF. Using 910 D7, a new anti-la antibody, we were able to observe directly the presence of la-positive lymphocytes and monocytes in normal peripheral blood and la-positive granulocyte precursor cells from 2 cases of chronic granulocytic leukemia (CGL) in transformation. The method is useful for immunophenotyping of cases of lymphoproliferative disorder (LPD) and for morphological identification of specific antigen-positive cells.

Antibodies, Monoclonal↗
PubMed1977

Conditions controlling the proliferation of haemopoietic stem cells in vitro.

A liquid culture system is described whereby proliferation of haemopoietic stem cells (CFU-S), production of granulocyte precursor cells (CFU-C), and extensive granulopoiesis can be maintained in vetro for several months. Such cultures consist of adherent and non-adherent populations of cells. The adherent population contains phagocytic mononuclear cells, "epithelial" cells, and "giant fat" cells. The latter appear to be particularly important for stem cell maintenance and furthermore there is a strong tendency for maturing granulocytes to selectively cluster in and around areas of "giant fat" cell aggregations. By "feeding" the cultures at weekly intervals, between 10 to 15 "population doublings" of functionally normal CFU-S regularly occurs. Increased "population doublings" may be obtained by feeding twice weekly. The cultures show initially extensive granulopoiesis followed, in a majority of cases, by an accumulation of blast cells. Eventually both blast cells and granulocytes decline and the cultures contain predominantly phagocytic mononuclear cells. Culturing at 33 degrees C leads to the development of a more profuse growth of adherent cells and these cultures show better maintenance of stem cells and increased cell density. When tested for colony stimulating activity (CSA) the cultures were uniformly negative. Addition of exogenous CSA caused a rapid decline in stem cells, reduced granulopoiesis and an accumulation of phagocytic mononuclear cells.

Animals↗
PubMed1996

Granulocytic sarcoma (chloroma): a report of two cases.

Granulocytic sarcoma or chloroma is defined as an extramedullary solid tumor, composed of granulocytic precursor cells at various levels of differentiation. Granulocytic sarcoma is mostly associated with acute and chronic leukemia, rarely with polycythemia vera and myelofibrosis. The use of special immuno-histochemical stains is mandatory, because this tumor is often misdiagnosed as malignant lymphoma. We report two cases of granulocytic sarcoma (tonsil and ovary) associated with chronic myelogenous leukemia. We describe the first reported association of atypical CML and granulocytic sarcoma.

Adult↗
PubMed1983

Effect of cancer chemotherapeutic agents on the chemiluminescence of human granulocytes.

21 unilateral breast cancer patients taking different combinations of chemotherapeutic agents (cyclophosphamide, methotrexate, 6-fluorouracil, vincristine, and prednisone) were studied to determine how chemotherapy affected their granulocytes. It is widely believed that in cancer patients chemotherapeutic agents increase susceptibility to infection. Therefore, luminol-enhanced chemiluminescence was used to evaluate leukocyte function since the chemiluminescence response has been correlated to bacterial killing. the chemiluminescence response in cancer patients (6-week treatment) was significantly reduced (approximately 50%; p less than 0.01) compared to nontreated volunteers. Preliminary studies using 3H-formyl-methionyl-leucyl-phenyl alanine binding showed similar decreases. We postulate that chemotherapy for 6 weeks may affect granulocyte precursor cells in bone marrow, thereby weakening peripheral granulocytes and reducing both their bactericidal capacity and 3H-formyl-methionyl-leucyl-phenyl alanine receptors.

Adult↗
PubMed1990

[The effect of the bone marrow fibroblasts from patients with malignant diseases of the blood system on the colony-forming capacity of granulomonocytic precursor cells].

The inhibiting activity of bone marrow fibroblasts and their ability to sustain survival of granulocytic cell precursors have been studied in patients with chronic myelocytic leukemia, chronic lymphoproliferative disorders, acute leukemia, myelodysplastic syndrome. Fibroblast conditioned medium inhibits proliferation of granulomonocytic precursors stimulated by leucocyte feeder layer or leucocyte conditioned medium. The effect depends both on the presence of monocytes and the specificity of the disease. The inhibitory effect is related with long-ranged factors. Bone marrow fibroblasts are able to sustain survival of hemopoietic precursors via humoral and cell-cell mechanisms. The regulatory role of bone marrow fibroblasts in hemopoietic disorders is discussed.

Bone Marrow↗
PubMedDate not supplied

Granulocytic sarcoma with pleural involvement. Identification of neoplastic cells with cytochemistry.

Malignant cells were detected in the pleural effusion of a patient with three separate primary malignancies. These cells were judged by conventional morphologic studies to be poorly differentiated cells, but cytochemical studies showed them to be granulocytic precursor cells. The use of cytochemical or immunochemical techniques may be most practical for the cytodiagnosis of malignant cells in serous effusions.

Biopsy↗
PubMed1980

Prediction of chemotherapy response in human leukemia using an in vitro chemotherapy sensitivity test on the leukemic colony-forming cells.

An in vitro test system to quantitatively assess the chemotherapy sensitivity of human acute leukemic colony-forming cells (L-CFU) in relation to normal granulocytic precursor cells (CFU-C) has been developed. After simultaneous exposure of leukemic and normal bone marrow cells to individual drugs in vitro, cells were grown using an improved agar culture method with daily feeding. A sensitivity index (SI) was determined as the ratio of survival fraction of CFU-C to that of L-CFU, L-CFU being more (or less) sensitive than CFU-C if the SI were higher (or lower) than unity. Thirty SI were determined for 6 single drugs actually given in various combinations to a total of 9 patients (8 with acute nonlymphocytic leukemia and 1 with chronic myelomonocytic leukemia). A highly significant correlation was observed between high (or low) SI and achievement of (or failure to achieve) complete remission, with only 6 false correlations (p = 0.0013). Also, the mean of these SI (MSI) for the multiple single drugs given to each patient as components of a combination chemotherapy was used to indicate an overall sensitivity for each trial of the chemotherapy. Among the 10 chemotherapy trials (1 trial each for 8 patients and 2 trials for 1 patient), 4 trials resulting in complete remission had MSI higher than 1.0, and 6 trials not resulting in complete remission had MSI lower than 1.0 (p = 0.0048). This assay system appears useful in predicting the response of patients to chemotherapy and in the selection of the most effective drugs for use in individual patients.

Adult↗
PubMed1987

Differentiation of myeloid cells in liquid culture: 2. Acute myelocytic leukemia cells.

In a companion paper we demonstrated that normal peripheral blood granulocytic precursor cells differentiate after 2-3 weeks in suspension culture. In the studies described here leukemic blast cells obtained from 14 patients with acute myelocytic leukemia (AML) and two patients with chronic myelocytic leukemia in blastic crisis were cultured in McCoy's 5A medium containing 15 per cent fetal bovine serum for 2-3 weeks at 37 degrees C in an atmosphere of 5 per cent CO2-95 per cent room air. 'Spontaneous' myeloid differentiation (20 x 10(4) viable mature myeloid cells ml-1) occurred in the cultures of cells obtained from 8 pts. The differentiation was granulocytic in three cases, monocytic in four cases and of mixed type in one case. Differentiation was independent of the growth of the cells in culture and occurred in four cases after the first week. Monocytic differentiation was seen only in AML of the FAB M4 type whereas granulocytic or mixed differentiation were seen only in AML of the FAB M1 or M2 types. When PHA leucocyte conditioned medium (PHA-LCM) was added to the cultures monocytic/macrophage differentiation was favoured. Inducers of the differentiation of the HL-60 cell line (N-methylacetamide, cytosine arabinoside, or retinoic acid) had no consistent effect on the differentiation and were at times inhibitory. Three patients received therapy with low dose cytosine arabinoside and no correlation was observed between the outcome of the treatment and leukemic cell differentiation in culture in the presence of the drug.

Bone Marrow↗
PubMed1982

Cytotoxicity of cytosine arabinoside on mouse progenitor stem cells.

In vitro colonogenic assay of mouse marrow granulocytic progenitor cells (spleen and agar colony forming cells) was carried out to determine the cytotoxic effect of 1-B-D-arabinofuranosyl cytosine on granulopoiesis. Mainly, the drug cytotoxicity on progenitor cells depended upon exposure time. Endotoxin stimulated colony forming cells showed enhanced cytotoxicity with shorter (25 min) exposure time as compared to a longer exposure of 60 min. A 60 min exposure was found to give maximum cytotoxic effect on spleen colony forming cells. With prolonged incubation, the cytotoxic effect of the drug on spleen colony forming and agar colony forming cells was more or less the same. Incubation of granulocytic precursor cells with the cytotoxic drug, in vitro, produced effects similar to those previously reported with in vivo drug administration. Therefore, some of these techniques can be employed as improved screening models for evaluating the cytotoxic agents in clinical trials.

Animals↗