Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation by thalidomide [N(alpha)-phthalimidoglutarimide] of tumor necrosis factor (TNF)-alpha production was found to be inducer-specific. Thalidomide enhances TNF-alpha production by human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while it inhibits TNF-alpha production induced with okadaic acid (OA) in the same cell line. Some phthalimide analogs, included PP-33 [2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione] and its 4,5,6,7-tetrafluora derivative FPP-33), also showed such an inducer-specific bidirectional TNF-alpha production-regulating activity. The structure-activity relationships of the compounds tested are similar, but not identical, in the TPA-stimulated HL-60 and OA-stimulated HL-60 assay systems.
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PMID:Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production. 870 5

Macrophages and their products may exert either inhibitory or stimulatory effects on malignant cells,thus preventing or supporting tumor growth, however, the mechanisms of this interaction are not fully understood. It was the aim of the present study to elucidate the role of macrophage activation during the growth and rejection of highly immunogenic murine leukemia P388/adria cell line which was made resistant by suboptimal treatment of mice with adriablastin during the serial passaging of parental P388 cells. The functional activity of peritoneal macrophages and the serum level of cytokines IL-1 beta, IL-6 and TNF-alpha were studied in different groups of mice. Mice from group 1 (control) received saline. Mice from group 2 (tumor bearers) with fast subcutaneous (s.c) 100% tumor growth were compared with animals from group 3 that had been twice previously immunized with lethally irradiated P388/adria cells and later inoculated with viable tumor cells. Tumors grew in only 25% of group 3 animals with a significant delay. The activity of peritoneal macrophages was studied by NO2- production and the NBT-test. Both tests revealed the early high systemic activation of macrophages in group 2. This coincided with the elevation of serum TNF-alpha and IL-6 levels. This effect was not dependent on whether alive or lethally irradiated tumor cells were inoculated. The NO2- production by peritoneal macrophages correlated well with the dynamics of serum cytokine levels while the NBT-test did not. Studies on group 3 showed total abrogation of early macrophage and cytokine reactions. The production of inhibitory factors by macrophages in previously immunized mice is suggested. The fact that the early activation of macrophages and increase of serum levels of proinflammatory cytokines occurred in animals with fast growing tumors, which was decreased or absent in animals with tumor delay or rejections, allows us to suppose that this reaction plays more a supporting than a protecting role for tumor growth.
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PMID:Involvement of macrophages and cytokines into rejection mechanism of the drug-resistant and immunogenic murine lymphoma P388/adria. 871 29

Serum levels of cytokines and in vitro cytokine production by lymph node mononuclear cells (LNMC) were studied in four patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD) or AILD-type T cell lymphoma. An increased level of serum interleukin-6 (IL-6) was detected on initial diagnosis in both of two patients examined. Spontaneous production of IL-6 by LNMC was detected in all four patients studied. Immunosuppressive therapy with cyclosporin A (CsA) was attempted in a 68-year-old man, who was refractory to intensive combination chemotherapy. The increased level of IL-6 in this patient decreased to normal within 3 weeks of CsA administration and the patient became symptom-free. One and a half months later, the IL-6 level gradually increased along with clinical exacerbation. We also measured serum levels of IL-1 alpha, IL-2, IL-4, IFN-alpha, gamma and TNF-alpha in parallel with IL-6, but these factors were only sporadically detected. IL-6 production by LNMC was stimulated by IL-2 but inhibited by CsA. These observations suggest that IL-6 is one of the important cytokines to be involved in the pathophysiology of AILD and CsA is a useful reagent for relieving symptoms.
Leukemia 1996 Sep
PMID:Increased levels of interleukin-6 (IL-6) in serum and spontaneous in vitro production of IL-6 by lymph node mononuclear cells of patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD), and clinical effectiveness of cyclosporin A. 875 70

We have recently established a new Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) cell line, designated Z-33. This line has L2 morphology, ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived. In addition, a rearranged immunoglobulin heavy-chain gene (JH) band was found in Z-33 cells by Southern blot analysis, confirming B cell clonality. Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2). Polymerase chain reaction (PCR)-amplified cDNA from Z-33 cells demonstrated an e1-az BCR-ABL junction, and the p190BCR-ABL protein was detected in them by the immune complex kinase assay. Z-33 cells produce interleukin (IL)-1 beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, Neither IL-1 beta, G-CSF, TNF-alpha, nor their corresponding antibodies affected the cell line's growth. In contrast, anti-GM-CSF neutralizing antibodies suppressed Z-33 colony formation, and GM-CSF stimulated it in a dose-dependent fashion. In addition, receptor studies with biotinylated GM-CSF demonstrated specific binding to Z-33 cells, indicating that the cells express GM-CSF receptors. Taken together, our data suggest that the Ph1-positive Z-33 ALL cells produce GM-CSF, express GM-CSF receptors, and show an autocrine proliferative response to this cytokine.
Leukemia 1996 Sep
PMID:Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line (Z-33) with an autocrine response to GM-CSF. 875 77

Regulation by thalidomide and phenylphthalimide analogs (FPP-33 and PPS-33) of TNF-alpha production is specific to cell type and to inducer, i.e., (i) the compounds enhance TPA-induced TNF-alpha production by human leukemia HL-60 cells, while they inhibit TPA-induced TNF-alpha production by another human leukemia cell line, THP-1, and (ii) the compounds inhibit TNF-alpha production by both HL-60 and THP-1 cells when the cells are stimulated with okadaic acid (OA). The structure-activity relationships of these compounds are similar in the four assay systems (TPA/HL-60, TPA/THP-1, OA/HL-60, and OA/THP-1). However, optically active analogs, (S)- and (R)-alpha-methylthalidomides, show distinct bidirectional regulatory effects on TNF-alpha production, i.e., only the (S)-form shows TNF-alpha production-enhancing activity in the TPA/HL-60 assay system, while the (R)-form shows much more potent TNF-alpha production-inhibiting activity than the (S)-form in the other assay systems.
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PMID:Cell type-/inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production and its enantio-dependence. 880 53

Benzylphthalimide analogs (P1P's) and phenethylphthalimide analogs (P2P's) have been found to exhibit thalidomide-like activity on the production of tumor necrosis factor (TNF)-alpha by the human leukemia cell line, HL-60, stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA). Structure-activity relationships are discussed on the basis of the TNF-alpha production-enhancing activity. Benzylphthalimide (P1P-00) exhibited which is weaker than that of thalidomide, but introduction of a methyl group at the ortho-position of the benzyl moiety (P1P-10) resulted an increase to a level comparable with that of thalidomide. Phenethylphthalimide (P2P-00) is more potent than thalidomide, and its fluorinated derivative, 2-phenethyl-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione (FP2P-00), exhibited potent activity at very low concentrations.
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PMID:Benzylphthalimides and phenethylphthalimides with thalidomide-like activity on the production of tumor necrosis factor alpha. 884 11

Dendritic cells (DC), as professional antigen-presenting cells, play a major role in stimulating naive T cell responses in vivo and in vitro, and may exacerbate or modulate T lymphocyte-mediated reactions, such as interactions between a hematopoietic graft and the recipient, eg GVHD and graft-versus-leukemia. Here, we describe a two-stage cell culture system for expansion of functionally active human DC from CD34+ marrow precursors. Optimal outgrowth was achieved by initially culturing CD34+ cells for 5 days in medium containing GM-CSF, MGF and TNF-alpha. Substitution of CD40L and IL-4 for TNF-alpha during a subsequent 5-day subculture increased DC content, such that by 10 days the cultures contained approximately 40% DC as determined by immunophenotype and morphology. An increase in DC purity to 84% at 10 days was achieved by immunomagnetic separation for CD1a+ cells from 5-day cultures and subculturing these cells in medium with IL-4 and CD40L. Reversing the sequence of growth factors during culture and subculture decreased the yield and purity of DC. Expression of CD80 and CD86 was enhanced by adding CD40L and IL-4, and the DC showed stimulatory activity in MLC. In conclusion, we have described a simple two-stage culture system to generate functional DC from CD34+ marrow precursors.
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PMID:In vitro expansion and characterization of dendritic cells derived from human bone marrow CD34+ cells. 893 57

We examined the effect of diffusible factors generated during the culture of the KM102 stromal cell line as well as in long-term bone marrow culture (LTBMC) on K562 leukemia cells, with respect to proliferation of clonogenic cells as well as total cells, and compared it with the effect on normal myeloid progenitors (CFU-GM). Proliferation of K562 cells plated in diffusion chambers was inhibited by coculture for 3-5 days in the fluid phase of stromal cell cultures or stromal cell-conditioned medium (CM), while CFU-GM proliferation was not inhibited under the same culture conditions. The inhibitory action was not attributed to the exhaustion of nutrients or growth promoting factors such as stem cell factor. These findings suggest that bone marrow stromal cells secrete diffusible molecule(s) which exert a preferential inhibitory effect on K562 leukemic cells vs. normal CFU-GM. Neutralization with antibodies against hematopoiesis-inhibiting cytokines such as TGF-beta 1, IFN-gamma, MIP-1 alpha and IL-4 which were detected in stromal cell-CM, failed to abrogate the inhibitory effect of KM102-CM on K562 cells. IL-1, TNF-alpha, IFN-alpha and lipopolysaccharides, known as stimulators of various cytokines from stromal cells, could not enhance the inhibitory activity. Further characterization of the factors may have implications for the treatment of leukemias.
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PMID:Preferential inhibitory effect of soluble factor(s) in human bone marrow stromal cells on proliferation of K562 leukemia cells versus normal myeloid progenitor cells. 893 34

We examined the effects of a cell-permeable ceramide analog, C2-ceramide, on the growth of TNF-alpha-resistant B lymphoma Raji cells lacking TNF-alpha-receptors (TNF-R). C2-ceramide inhibited the clonal growth of not only TNF-alpha-sensitive myeloid leukemia cells (HL60 and U937) but also Raji cells. Following stimulation with C2-ceramide, HL60 and U937 cells showed apoptotic cell death, whereas Raji cells did not show a detectable level of apoptosis. However, a cell-cycle arrest in G0/G1 phase was observed in Raji cells after the treatment with C2-ceramide, which was accompanied by the dephosphorylation of retinoblastoma (RB) gene products and decreased expression of p53 proteins. Failure of C2-ceramide to induce apoptosis in Raji cells might be explained by the lack or low expression of apoptosis-inducing proteins by two lines of evidence: (1) Raji cells were resistant to apoptosis induced by ceramide even in the presence of transcription/translation inhibitors; (2) Bax protein expression was not detectable in Raji cells, although Bcl-2 protein expression in Raji cells was even less than that in HL60 and U937 cells. Moreover, protein kinase C (PKC), whose activation has been described to inhibit ceramide-induced apoptosis, inhibitor H-7 did not induce apoptotic cell death in Raji cells, suggesting that an imbalance between PKC and ceramide pathways is not the reason for the resistance of Raji cells against ceramide-induced apoptosis. Finally, ceramide-induced activation of nuclear factor kappaB (NF-kappaB) was observed in Raji cells as well as HL60 cells, indicating that activation of this molecule may not be specific for apoptosis. By using the present model, one can dissect cell-cycle arrest and apoptosis induced by ceramide.
Leukemia 1996 Dec
PMID:Cell-permeable ceramide inhibits the growth of B lymphoma Raji cells lacking TNF-alpha-receptors by inducing G0/G1 arrest but not apoptosis: a new model for dissecting cell-cycle arrest and apoptosis. 894 36

We have selected an etoposide-resistant variant (CCRF-CEM/VP-16) of the human T-lymphoblastic CCRF-CEM leukemia for study. Resistance to the topoisomerase II (topo II) inhibitor was about 11-fold and stable. Other data revealed that the new cell line had acquired an atypical, non-P-glycoprotein overexpressing multidrug resistant (MDR) phenotype with cross-resistance to other topo II inhibitors (amsacrine, doxorubicin, and mitoxantrone) and to glucocorticoids, but not to novobiocin, ICRF-187, vincristine or cisplatin. In a first instance, we assumed that altered drug-topo II interactions, based on quantitative and/or qualitative modifications of the enzyme, are a cause of resistance in the cell line. We tried to modify the drug sensitivity of the cells by means of various agents and cytokines. Positive results were obtained with verapamil and, to a lesser extent, cyclosporin A, but they were not specific for the drug resistant variant and occurred in the parental CCRF-CEM as well. Other attempts with buthionine sulfoximine, novobiocin, pentoxifylline, interleukin-1, interferon-alpha, retinoic acid, TNF-alpha, bryostatin 1 or phorbol myristate acetate were substantially unsuccessful, thus confirming the difficulty of pharmacologically overcoming atypical MDR. More encouragingly, however, CCRF-CEM/VP-16 cells exhibited hypersensitivity to other agents, including actinomycin D and taxol.
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PMID:Development and partial characterization of a human T-lymphoblastic leukemic (CCRF-CEM) cell line resistant to etoposide. Analysis of possible circumventing approaches. 898 Nov 88


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