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PubMed1990

Differential toxicity of carbovir and AZT to human bone marrow hematopoietic progenitor cells in vitro.

We have studied the in vitro effects of carbovir as compared to 3'-azido-3'-deoxythymidine (AZT) on the growth of clonal bone marrow-derived hematopoietic progenitor cells. (-)Carbovir, the enantiomer with anti-human immunodeficiency virus (HIV) activity, exhibited significantly less toxicity to hematopoietic cells than AZT. These in vitro studies suggest that (-)carbovir will exhibit less hematologic toxicity in the therapy of patients infected with HIV either as a single agent or in combination with other agents that inhibit HIV proliferation.

Bone Marrow Cells↗
PubMed1985

Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas.

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for antiglioma activity of nitrosoureas and (b) myelosuppression is at least partly linked with carbamoylation but that structural entities in the carbamoylating isocyanate rather than a quantitative degree of carbamoylation determine the degree of potential myelotoxicity.

Alkylating Agents↗
PubMed1993

The influence of 4 degrees C storage on proliferative potential of human bone marrow CD34+ cells. Transplantological implications.

The possibility of storage of human bone marrow CD34+ cells at 4 degrees C was investigated for bone marrow transplantational purposes. The cells were placed in Iscove medium supplemented with 20% serum (15% bovine calf serum 5% human AB serum) for three weeks at 4 degrees C. During the storage time, clonogenecity of granulocyto-monocytic (CFU-GM) erythropoietic (BFU-E) and megakaryocytic (CFU-Meg) progenitors was investigated. It was found that it is possible to keep human CD34+ cells at 4 degrees C, at least for a few days before transplantation. At day four of the storage, the number of CFU-GM and BFU-E cells still exceeded 50% of the cells present at day 0. However, we have found that CFU-Meg in comparison to other progenitors are much more sensitive to metabolic storage stress. This enhanced sensitivity of megakaryocytic progenitors could explain, at least partially, the well known phenomenon of retardation of the thrombopoietic recovery in patients undergoing bone marrow transplantations.

Antigens, CD↗
PubMed1994

Balance between human peripheral blood CFU-GEMM and CFU-Meg in sustained and acute thrombocytopenia.

Quantitative variations of blood cell progenitors were studied in thrombocytopenic post-chemotherapy patients and in healthy plateletpheresis donors with the aim of better understanding the reasons for their varying presence in peripheral blood. In 6 post-chemotherapy patients with severe thrombocytopenia on days 21-27 after initiation of chemotherapy when white blood cell counts were approximately 2.1-6.0 x 10(9)/l, a balance was observed between the most and least immature progenitors: levels of CFU-Meg were significantly lower than control values whereas levels of CFU-GEMM were 2-fold higher than in controls. Results suggest that an activator distinct from the known poietins may stimulate very immature progenitors. In 15 plateletpheresis donors, numbers of CFU-GEMM and CFU-Meg were greatly increased, respectively 5.5-fold and 10-fold, following plateletpheresis. Data once again indicate a major role of CFU-GEMM in the production of mature blood cells. As the most immature progenitors and thrombocytopoiesis stimulating factor(s) are both present in peripheral blood, such factors may be responsible for the initial engagement of these very early progenitors into a specific cell line.

Acute Disease↗
PubMedDate not supplied

[The peripheral blood of frogs in the genus Rana as a test system for assessing environmental pollution].

Differential analysis of leukocytes was carried out peripheral blood smears of the frogs from four localities in the territory adjacent to a chemical plant in the Novgorod District (Rana temporaria) and two localities with an increased radiation background in the Bryansk District (R. lessonae and R. esculenta). Marked and similar changes in the content of neutrophilic and eosinophilic granulocytes were found in the frogs from all studied localities. A pronounced neutropenia was noted, which was often accompanied by the appearance of immature forms of the neutrophilic series. We propose that these changes are due selective damage of the entire series of differentiation of neutrophilic granulocytes, including the precursor cells. The increased percentage of eosinophilic granulocytes and appearance, in some cases, of immature cells are considered as signs of protective (antitoxic and antimicrobial) response.

Animals↗
PubMed1975

Immunoglobulins on the surface of blast cells in human acute leukemia.

By means of the direct fluorescent antibody technique it was shown that malignant cells in acute lymphoblastic leukemia do not, as a rule, bear immunoglobulins on the cell surgace (43 of 45 cases). During complete remission the number of Ig-positive cells corresponds to the number of Ig-positive cells in normal lymphocyte populations. During incomplete remission as well as during incomplete remission as well as during intensive chemotherapy, the lymphocyte-like cells are evidently malignant, since they do not contain a normal number of Ig-positive lymphocytes. In acute myeloblastic leukemia (AML) and acute myelomonoblastic leukemia (AMML), lymphocytes distribute normally according to the number of Ig-positive and Ig-negative in 34 of 38 cases. AMML blast cells were Ig-positive in nine of ten cases. The data are discussed in the light of current concepts about the presence of a common precursor cell of granulocytes and monocytes.

Absorption↗
PubMed1993

In vivo and in vitro effects of 3-hydroxypyridin-4-one chelators on murine hemopoiesis.

The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20). Administration of 60 doses of 200 mg/kg CP20 to Balb/c mice resulted in significant anemia, lymphopenia and granulocytopenia accompanied by bone marrow hypocellularity. DFO and CP94 (1,2,diethyl-HPO) at the same dose also caused lymphopenia but marrow cellularity was unaffected. When marrow from untreated mice was incubated with HPOs and DFO, erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony forming units (CFU-G+Mac), colony growth was inhibited in a dose-dependent manner at micromolar concentrations. The addition of iron to saturate the chelators abrogated the effects of DFO, but not those of the HPOs. With the HPO-iron complexes, addition of sufficient iron to saturate the transferrin in the medium reversed the inhibitory effects of the relatively hydrophilic CP20-iron complex but not those of the more lipophilic CP94-iron complex. Addition of further iron-saturated transferrin also corrected inhibition by the CP94-iron complex. These results show that HPO-iron complexes potentially have antiproliferative effects unlike DFO-iron complex (FO). The difference in the relative effects of CP20 to CP94 on hemopoiesis in vivo and in vitro suggests that additional factors to those inhibiting hemopoiesis in marrow cultures may operate with the long-term administration of iron chelators in vivo.

Animals↗
PubMed1996

The synthetic tetrapeptide AcSDKP protects cells that reconstitute long-term bone marrow stromal cultures from the effects of mafosfamide (Asta Z 7654).

The tetrapeptide AcSDKP (Seraspenide) has been described as an inhibitor of CFU-S entry into DNA synthesis; as a result, its administration can protect mice against lethal doses of cytosine arabinoside. We have studied the ability of AcSDKP to protect and promote the growth of early CD34+ human bone marrow (BM) stem cells in Dexter long-term cultures following exposure to a toxic concentration of mafosfamide. The protection assay was based on the preincubation of CD34+ BM cells with or without AcSDKP at 10(-10)M or 10(-8)M followed by exposure to a toxic dose of mafosfamide (100 micrograms/mL). The production of granulomonocytic progenitor cells (CFU-GM) was subsequently studied in long-term bone marrow cultures (LTBMC) of the samples exposed to mafosfamide and preincubated or not (control) with AcSDKP. After a lag of 2 to 3 weeks, the number of CFU-GM peaked at the 4th to 5th week in both the supernatant and the adherent layers. A greater production of granulomonocytic progenitor cells was observed in LTBMC from the samples preincubated with AcSDKP compared with control cells. Depending on the BM samples, enhanced production of CFU-GM in the AcSDKP-treated cell cultures was observed at either the 10(-10)M or 10(-8)M concentration. These results suggest that AcSDKP can protect in vitro human long-term culture-initiating cells (LTC-IC) from mafosfamide, resulting in an increased production of CFU-GM from this early stem cell compartment.

Amino Acid Sequence↗
PubMed1996

[Cytokines regulate apoptosis of leukemic cells].

It is clear that cytokines regulate normal hematopoiesis including proliferation, differentiation, and apoptosis (programmed cell death). Leukemia is a disorder of unbalance between excessive proliferation and inappropriate apoptosis. Leukemic cells are also stimulated by cytokines similar to normal hematopoietic cells. It is reported that the oncogenes and tumor suppressor genes are associated with not only leukemogenesis but also cell cycle, for example proliferation, differentiation, and apoptosis (programmed cell death). We found that G-CSF leads to apoptosis of radiation induced murine leukemia cell line (C2M-A5), and its apoptosis is dependent on cell cycle. From these results together with other related reports, cytokines seem to be a key substance of apoptosis of leukemic cells and the apoptosis inducing therapy will be a new strategy for leukemia therapy.

Animals↗
PubMed1989

Drug-induced agranulocytosis: review of possible mechanisms, and prospects for clozapine studies.

Although toxicity and inborn errors of metabolism may also be involved, immunological reactions play an important role in the induction of drug-induced agranulocytosis. Drug-induced antibodies may lead to agranulocytosis by at least three different immunological mechanisms. Immune complexes may selectively adhere to granulocytes or their immature precursor cells, the drug may bind to the granulocytes as carriers of the immunogenic drug and finally the drug may induce antibodies directed to granulocyte-specific structures. The use and the interpretation of in vitro assays to detect drug-dependent antibodies against granulocytes or myeloid precursor cells are discussed. These assays will be used to detect a possible immunological mechanism involved in clozapine-induced agranulocytosis. Further studies will concern the identification of possible genetic risk factors associated with clozapine-induced agranulocytosis.

Agranulocytosis↗
PubMed1990

[Hematopoietic stem cells (CFU-S) in retrovirus-induced murine malignant histiocytosis].

The murine malignant histiocytosis sarcoma virus (MHSV) is a replication-defective murine retrovirus which contains a ras-oncogen. Upon intravenous infection of normal adult NIH-mice a rapidly fatal systemic proliferation of transformed mononuclear phagocytes develops. We have investigated the involvement of other mature hematopoietic lineages and of hematopoietic stem cells during the course of the disease. The erythroid lineage is affected by a profound anemia which is temporarily accompanied by an increase of erythroid precursors in bone marrow and spleen and a final ablation of erythroid stem cells. A granulopenia occurs with a concurrent decrease of granulocytic precursors and stem cells. The platelets fall to very low levels early during the disease despite of an increase of megakaryocytes and megakaryocytic stem cells. Multipotential stem cells show temporarily a slight increase followed by an almost total terminal ablation. The results show that MHSV has distinct effects on other hematopoietic lineages apart from its transforming properties.

Animals↗
PubMed1998

Targeted disruption of the MYC antagonist MAD1 inhibits cell cycle exit during granulocyte differentiation.

The switch from transcriptionally activating MYC-MAX to transcriptionally repressing MAD1-MAX protein heterodimers has been correlated with the initiation of terminal differentiation in many cell types. To investigate the function of MAD1-MAX dimers during differentiation, we disrupted the Mad1 gene by homologous recombination in mice. Analysis of hematopoietic differentiation in homozygous mutant animals revealed that cell cycle exit of granulocytic precursors was inhibited following the colony-forming cell stage, resulting in increased proliferation and delayed terminal differentiation of low proliferative potential cluster-forming cells. Surprisingly, the numbers of terminally differentiated bone marrow and peripheral blood granulocytes were essentially unchanged in Mad1 null mice. This imbalance between the frequencies of precursor and mature granulocytes was correlated with a compensatory decrease in granulocytic cluster-forming cell survival under apoptosis-inducing conditions. In addition, recovery of the peripheral granulocyte compartment following bone marrow ablation was significantly enhanced in Mad1 knockout mice. Two Mad1-related genes, Mxi1 and Mad3, were found to be expressed ectopically in adult spleen, indicating that functional redundancy and cross-regulation between MAD family members may allow for apparently normal differentiation in the absence of MAD1. These findings demonstrate that MAD1 regulates cell cycle withdrawal during a late stage of granulocyte differentiation, and suggest that the relative levels of MYC versus MAD1 mediate a balance between cell proliferation and terminal differentiation.

Animals↗
PubMed1988

Effects of recombinant tumor necrosis factor, lymphotoxin, and immune interferon on proliferation and differentiation of enriched hematopoietic precursor cells.

We compared the effects of recombinant (r) tumor necrosis factor (TNF) and lymphotoxin (rLT) on in vitro colony formation by erythroid, multipotential and granulocyte, monocyte (CFU-GM) precursor cells. Recombinant granulocyte, macrophage-colony stimulating factor and bone marrow preparations enriched for hematopoietic precursors were used in order to examine the direct effects of the cytokines on precursors in the absence of other soluble factors or mature cells that may influence colony formation. Both rTNF and rLT inhibited colony formation by erythroid and multipotential precursor cells. rTNF and rLT did not inhibit the more mature (day-7) CFU-GM, although a synergistic inhibition was observed when the cytokines were added to cultures together with recombinant interferon gamma (rIFN gamma). However, rTNF did inhibit day-7 CFU-GM when conditioned medium from the human bladder carcinoma cell line 5637 was used as a source of colony-stimulating activity. rTNF inhibited the more immature (day-14) CFU-GM regardless of the source of colony-stimulating activity used, and was a stronger inhibitor of day-14 CFU-GM than rLT, suggesting a difference in the biological effects of the two cytokines. Noninhibitory concentrations of rTNF or rIFN increased the number of monocyte colonies formed, identified by cytochemical staining. These data suggest a mechanism for TNF and IFN gamma-induced inhibition of CFU-GM through induction of monocyte differentiation rather than through a direct toxic effect.

Bone Marrow Cells↗
PubMed1995

Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-alpha.

Human CD34+ bone marrow progenitors cultured in the presence of granulocyte-macrophage CSF (GM-CSF) develop along a myeloid pathway, and the addition of exogenous TNF-alpha leads to the differentiation of dendritic cells among the myeloid progeny. These bone marrow CD34+ -derived dendritic cell that develop during 2-wk culture have the same morphologic, phenotypic, and functional properties that distinguish mature dendritic cells in blood. c-kit ligand does not directly influence dendritic cell differentiation per se, but rather increases the total cell number in synergistic combination with GM-CSF and TNF-alpha. This degree of expansion translates into an effective yield of approximately 1.7 x 10(6) mature dendritic cells per single ml of normal adult human bone marrow, compared with approximately 10(6) dendritic cells usually obtained from 450 to 500 ml of peripheral blood. In addition to dendritic cells that constitute approximately 10 to 15% of the total myeloid progeny, the cultures contain monocytes/macrophages and intermediate granulocytic precursors. Monocytes/macrophages and dendritic cells together comprise all of the class II MHC-positive progeny. Sorted cells bearing the CD14+ HLA-DR+ phenotype of mature monocytes are at least 1.5 to 2 logs less active than CD14- HLA-DR+ dendritic cells as stimulators in the allogeneic MLR, even though both CD14+ and CD14- subpopulations share expression of several costimulatory ligands. The synergistic combination of c-kit ligand, GM-CSF, and TNF-alpha therefore expands substantial numbers of immunostimulatory CD14- HLA-DR+ dendritic cells from defined CD34+ progenitors in human bone marrow. This should facilitate the use of dendritic cells in the manipulation of T cell-mediated immune responses.

Antigens, CD↗
PubMed1988

Inhibitory activity of interleukin 2-activated lymphocytes on human granulocyte precursors (CFU-g).

Interleukin 2-activated lymphocytes (lymphokine-activated killer [LAK] cells) cultured from 2 to 14 days were added to the cultures of granulocyte precursors (CFU-g). The LAK cells inhibited colony formation of granulocyte precursors; LAK cells cultured for five days showed the strongest inhibitory activity on colony formation. The presence of cell-to-cell interaction between LAK cells and bone marrow mononuclear cells (BMNC) in CFU-g assays emphasized the LAK cell-derived colony inhibitory activity (LAK-CIA), but cell-to-cell interaction was not always a requirement for LAK-CIA, since LAK cells were also found to inhibit colony formation without such interaction. This report shows that LAK cells can inhibit in vitro colony formation of granulocyte precursors. We therefore concluded that the observed CIA is caused by soluble factor(s) derived from LAK cells, and that E-rosette-forming cells are manifesting LAK-CIA.

Colony-Forming Units Assay↗
PubMed2000

T lymphocytes from granulocyte colony-stimulating factor-/- mice produce large quantities of interferon-gamma in a chronic infection model.

Little is known about the role of granulocyte colony-stimulating factor (G-CSF) in the response to chronic bacterial infections. To address this we infected G-CSF knock out (G-CSF-/-) mice with Mycobacterium avium. Infection was not exacerbated in G-CSF-/- mice despite a deficiency in the total bone marrow cells, colony-forming haemopoietic cells, granulocytes and monocyte precursors in the bone marrow. Peritoneal cells from G-CSF-/- produced less nitric oxide (NO) upon culture in vitro with antigen than did wild-type (WT) cells. Unexpectedly, T cells from infected G-CSF-/- mice were able to produce significantly more interferon-gamma (IFN-gamma) than the wild type (WT) controls. T cells from G-CSF-/- mice still produced more IFN-gamma even when in vitro NO production was inhibited, while enzyme-linked immunospot assay (ELISPOT) assays showed more IFN-gamma-producing cells in the G-CSF-/- mice. This was confirmed by intracellular cytokine staining (ICCS), which showed that there were more IFN-gamma producing T cells in vivo in the G-CSF-/- than the WT controls following M. avium infection. It is possible that a deficit of NO in vivo allows T cells to develop a higher IFN-gamma-producing phenotype. Thus we show a novel relationship between G-CSF and IFN-gamma production by T cells revealed in this chronic bacterial infection model.

Animals↗
PubMedDate not supplied

[Role of hematopoietic microenvironment in the mechanism of radioprotective action of interleukin-1 beta in long-term bone marrow cultures].

The influence of human interleukin-1 beta in different concentration on processes of postirradiation recovery of haemopoietic precursors (GM-CFC) and morphology of recognized elements of bone marrow were studied in long-term bone marrow cultures during 28 days after gamma-irradiation with a dose of 2 Gy. It was studied also the action of interleukin-1 beta on proliferation, the contents of GM-CFC and the induction of GM-CSF in non-irradiated cultures. It was shown that the injection of interleukin-1 beta increased proliferation and the content of GM-CFC and also raised an induction of GM-CSF in the non-irradiation cultures. The maximum increase of a level of GM-CSF, amount of GM-CFC and proliferation of GM-CFC was marked in 20 hours after the injection of cytokine. Under irradiation of long-term bone marrow cultures the maximum stimulation effect to recovery of GM-CFC, total number of myelocaryocytes and the content of immature and mature granulocytes were observed after the injection of interleukin-1 beta in concentration of 0.005 microgram/ml 20 hours prior to radiation exposure. The data of this report suggest that one of the mechanisms of radioprotective action of interleukin-1 beta apparently is connected with stimulation action on hematopoietic microenvironment cellular elements that causes the release of GM-CSF or/and other cytokines, and stimulation recovery of haemopoietic precursors.

Animals↗