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)

Patients with chronic myelogenous leukaemia (CML) in untreated chronic phase are deficient in their ability to generate lymphokine-activated killer (LAK) cells from peripheral blood mononuclear cells although they possess essentially normal levels of CD16+ and Leu19+ lymphocytes, which do not seem to be actively suppressed by tumour cells. Attempts to enhance LAK cell generation in these patients are reported here. Combining the lymphokines interleukins-2, with -4 and -5 (IL-2, IL-4, IL-5), was not successful; in fact, IL-4 depressed LAK cell induction in both normal donors and CML patients. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate also failed to enhance cytotoxicity of normal donors or patients, and indomethacin was similarly without effect. The only agent found to enhance LAK cell induction by IL-2 in normal donors was interferon-gamma (but not IFN-alpha) and even this modest effect was not seen with the cells of CML patients. Increasing concentrations of IL-2 and/or culture duration also failed to improve LAK cell generation by patients. The only improvement in LAK cell generation was observed in CML patients treated for one or more months with IFN-alpha, where a steady increase of LAK activity with time after initiation of therapy was noted. These results show that the blockade of LAK cell induction in chronic-phase myelogenous leukemia patients is difficult to lift pharmacologically in vitro but possibly susceptible to biological response modifiers in vivo.
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PMID:Partial correction of defective generation of lymphokine-activated killer cells in patients with chronic myelogenous leukaemia after in vivo treatment with interferon-alpha (Wellferon). 278 1

We studied the in vivo antitumor effects of natural human tumor necrosis factor-alpha (nHuTNF-alpha) and natural human interferon-alpha (nHuIFN-alpha), both of which were produced by HVJ (hemagglutinating virus of Japan)-stimulated acute lymphatic B cell leukemia line, BALL-1 cells. To clarify the interaction between nHuTNF-alpha and nHuIFN-alpha, we used novel experimental models of lung metastasis and intraabdominal carcinomatosis which we developed in nude mice using a human tumor line, RPMI 4788. While the intravenous administration of nHuTNF-alpha or nHuIFN-alpha alone inhibited lung metastasis, the two cytokines given in combination synergistically inhibited lung metastasis. In a comparative study, nHuTNF-alpha and recombinant human interferon-gamma (rHuIFN-gamma) in combination also synergistically inhibited lung metastasis. Treatment with nHuTNF-alpha and nHuIFN-alpha combined significantly prolonged the survival of nude mice with intraabdominal carcinomatosis. Complete regression of five different human tumor xenografts was achieved by the simultaneous intratumoral injection of nHuTNF-alpha and nHuIFN-alpha. Histological examination revealed that tumor cell lysis occurred 24 h after the intratumoral administration of the cytokines. No significant signs of toxicity to nude mice were observed at any dose tested. The synergism of nHuTNF-alpha and nHuIFN-alpha may allow treatment at a relatively low dose range, thus minimizing side effects. The wide range of anticancer activity of these agents may provide better therapeutic efficacy. The in vivo assay systems which we have developed are useful for the analysis of the biological activities and interactions of cytokines and chemotherapeutic drugs.
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PMID:Antitumor effect of natural human tumor necrosis factor-alpha and natural human interferon-alpha in combination against human cancer transplanted into nude mice. 280 Nov 85

Culture supernatant from a human T-cell leukemia virus type I (HTLV-1)-infected cell line, DGA-1, contained a novel macrophage-activating factor (MAF). This MAF was antigenically and functionally distinct from interferon-gamma (IFN-gamma) and from granulocyte-monocyte colony-stimulating factor (GMCSF). Potential contaminants such as bacterial lipopolysaccharide (LPS), Mycoplasma spp, and HTLV-1 were not responsible for this MAF activity. The DGA-1 MAF was secreted constitutively and the cell line grew well in the absence of growth factors such as interleukin-2, mitogen, or antigen. This cell line should provide a good source of this MAF for further purification and characterization.
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PMID:A novel human macrophage-activating factor: distinction from interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GMCSF). 283 73

Adult T-cell leukemia (ATL) is one of the most difficult diseases to treat because of severe underlying immune deficiency and metabolic disturbance. Interferon has potent antiviral, antiproliferative, and immunomodulating properties, and therefore, this may be a good agent to treat such immune deficient patients with peripheral T-cell leukemia. During a period from April 1984 to August 1985, six patients were treated with interferon-beta (IFN-beta), and interferon-gamma (IFN-gamma) was given to five patients. Three patients achieved partial remission by IFN-beta administration with a response duration of 1, 1.5, and 12 months respectively, whereas one complete remission and two partial responses were experienced by IFN-gamma treatment with 4, 4, and 2 months of response. Side effects of IFN-beta were similar to those of IFN-gamma including fever, chills, fatigue, mild hematologic depression, and transient hepatic enzyme abnormalities. These promising results warrant further well-designed clinical trials including combination with other agents or modalities of treatment.
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PMID:Recombinant interferon beta and gamma in the treatment of adult T-cell leukemia. 288 Jun 55

We have used a lymphokine-responsive clone (3B3) of B leukemia cells (BCL1) to examine the effects of several recombinant and purified lymphokines. Cells from BCL1-3B3 were induced to secrete IgM in the presence of recombinant interleukin 2 (rIL 2) (10 to 50 U/ml); a concomitant increase in proliferation was observed. Recombinant interferon-gamma (rIFN-gamma) was a potent inhibitor of proliferation. In addition, rIFN-gamma did not induce an increase in IgM secretion and, when added to rIL 2-stimulated BCL1-3B3 cells, completely blocked IgM secretion at a concentration of 10 U/ml. Purified and recombinant IL 1 (rIL 1) had no significant effect on differentiation either alone or in combination with rIL 2 and/or rIFN-gamma. However, rIL 1 was able to synergize with rIL 2 in enhancing the proliferation of BCL1-3B3. The ability of cells to respond to rIL 2 was limited to the in vitro (Ly-1+) clones of BCL1 cells since the in vivo derived (Ly-1-) BCL1 cells did not differentiate in response to IL 2. Consistent with their functional response to rIL 2, cells from the in vitro clone (3B3) are IL 2-receptor-positive (IL-2R+) and the in vivo derived BCL1 cells are IL-2R-. A second set of neoplastic B cell clones derived from the AKR 225 lymphoma did not respond to rIL 2 even though they expressed receptors for IL 2 and could be induced by T cell supernatant to secrete IgM, thus indicating that expression of IL 2R is not the sole requirement for IL 2 responsiveness. The monoclonal anti-IL 2R antibody (7D4) mimicked IL 2 in its ability to stimulate differentiation of BCL1-3B3 cells. These data suggest that rIL 2 and the monoclonal anti-IL-2R antibody are capable of inducing a differentiative response in the Ly-1+ BCL1-3B3 cells that is functionally equivalent to the response evoked by the previously described lymphokine B cell differentiation factor for IgM (BCDF mu). Thus, two distinct lymphokines appear to be providing a similar signal to a clonal neoplastic B cell population. Furthermore, rIL 2 is capable of providing both a proliferative and a differentiative signal.
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PMID:Recombinant IL 2 but not recombinant interferon-gamma stimulates both proliferation and IgM secretion in a Ly-1+ clone of neoplastic murine B cells (BCL1). 294 63

The human monoblast leukemia line U937 is growth inhibited and induced to express various characteristics of mature monocytes by lymphokines (LK) and other cytokines. Previous experiments have shown that interferon-gamma (IFN-gamma) is responsible for some but not all of the differentiation-inducing effects on U937. To determine the variety and specificity of activity, the following factors were studied: phytohemagglutinin-induced LK that contained IFN-gamma (100 units/ml); purified IFN-gamma; human colony-stimulating factor 1 (CSF-1); and conditioned medium(a) (CM) from the human bladder carcinoma cell line 5637 and the hepatoma cell line SK-HEP. LK preparations contained no colony-stimulating activity, whereas CM from 5637 and SK-HEP both contained granulocyte-macrophage CSF (3000 to 4000 units/ml) but no IFN activity. IFN-gamma is the major immunoglobulin G Fc receptor-inducing species within lymphokine, since anti-interferon-gamma antibody inhibited most of this activity. Other sources of Fc receptor-inducing activity were CM from SK-HEP and 5637 cell lines. Human CSF-1 when tested up to 800 units/ml was inactive for Fc receptor induction. LK induced the chemotactic peptide receptor, but this induction was due to factors other than IFN-gamma as anti-IFN-gamma antibody did not inhibit the induction, and purified IFN-gamma at a dose equivalent to that found in LK (100 units/ml) had no activity in the assay. SK-HEP and 5637 CM had strong chemotactic peptide receptor-inducing activity, but human CSF-1 was inactive up to 800 units/ml. Peroxide production after stimulation with phorbol myristic acid could be induced by LK, LK with anti-IFN-gamma antibody, 5637, and SK-HEP treatment. IFN-gamma (100 units/ml) and CSF-1 (800 units/ml) were ineffective. Peroxide production was induced by IFN-gamma at concentrations above 1000 units/ml. The inducibility of several enzymatic activities was determined as additional measures of maturation. N-Acetylglucuronidase was induced, for example, by LK, IFN-gamma, 5637 CM, and phorbol myristic acid. Alkaline phosphatase was induced by LK, IFN-gamma, dexamethasone, and phorbol myristic acid. 1,25-Dihydroxycholecalciferol was also examined and could induce most of the maturational markers examined. The results demonstrate that non-IFN cytokines from several sources have profound differentiation-inducing effects on monoblast leukemia cells in a pattern different from that of IFN-gamma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Distinct activities of interferon-gamma, lymphokine and cytokine differentiation-inducing factors acting on the human monoblastic leukemia cell line U937. 298 Nov 61

The results presented here indicate that recombinant murine interferon-gamma can cause a dramatic differential induction of two distinct class I MHC molecules. Thus, IFN-gamma treatment of the murine leukemia virus (MuLV)-induced AKR SL3 tumor, a cell line that normally expresses moderate levels of class I MHC antigens, resulted in a large increase in H-2Dk expression, but no change or a slight decrease in H-2Kk expression as measured by cytofluorography. Explanations of the selective enhancement of Dk expression based on increased Fc receptor display or differential kinetics of induction were ruled out. The phenomenon was observed over a wide range of doses of IFN-gamma and with two different monoclonal antibodies to Kk, the latter finding making it unlikely that an altered form of the Kk molecule was induced. The same differential induction of the Dk antigen was observed for the LBRM.5A4 tumor cell line. Because LBRM.5A4 is also MuLV+ but of congenic B10.BR (H-2k) origin, these results were consistent with the possibility that such differential induction was associated with the H-2k haplotype and/or MuLV. The implications of these results, as a possible mechanism of tumor cell escape from an immune surveillance system monitored by class I MHC-restricted T cells and as a useful model system to dissect the mechanism of IFN-gamma induction of class I MHC antigens, are discussed.
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PMID:Differential induction of H-2K vs H-2D class I major histocompatibility complex antigen expression by murine recombinant interferon-gamma. 308 10

Tumor Necrosis Factor (TNF), released by induced macrophages, causes tumor necrosis in animals, and preferentially kills transformed cells in vitro. Using pure, recombinant human TNF, we report here its cytotoxic action on several human transformed and non-transformed cell lines. Furthermore, remarkable synergism between TNF and interferon-gamma (IFN-gamma) was observed in a large number of human cell lines, especially breast, cervix and colon carcinomas. Some other human cell lines, not sensitive to TNF alone, became highly sensitive when IFN-gamma was present as well. We could not demonstrate a synergism between TNF and IFN-gamma on any of the lymphoma/leukemia cell lines tested. All normal human, non-transformed diploid cell lines were insensitive to TNF even in the presence of IFN-gamma. This study also confirms the observation that inhibition of protein synthesis by metabolic drugs (e.g. actinomycin D) remarkably enhances the sensitivity of several target cell lines to cytolysis by TNF.
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PMID:Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. 308 2

Cultured human macrophages from normal donors were examined for their capability to metabolize 25-hydroxyvitamin D3 (25-(OH)D3). Upon exposure to recombinant human interferon-gamma (IFN-gamma) both bone marrow-derived macrophages (BMM) and pulmonary alveolar macrophages (PAM) produced a polar 25-(OH)D3 metabolite which was purified from conditioned media and unequivocally identified as 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) by UV-absorbance spectrophotometry and mass spectrometry. The BMM and PAM also synthesized a second 25-(OH)D3 metabolite which was structurally identified as 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3). The time course of 25-(OH)D3 metabolism by macrophages suggested that the production of 24,25-(OH)2D3 was stimulated by high intracellular levels of 1,25-(OH)2D3 and not by IFN-gamma. The 1,25-(OH)2D3 obtained from BMM and PAM promoted macrophage-like differentiation of promyelocytic HL-60 leukemia cells and inhibited IFN-gamma production by normal human lymphocytes. Our data suggest that locally high levels of 1,25-(OH)2D3 in the microenvironment of IFN-gamma-stimulated BMM and PAM may modulate the function of hormone-responsive cells.
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PMID:Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages. 311 52

Histamine acts directly on human T cells to inhibit lymphokine production without the involvement of accessory cells. Histamine inhibits the production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) by purified human peripheral T cells activated in the presence of either intact monocytes or metabolically inactive fixed Raji and U698 cells as accessory cells. Purified T cells do not respond more than marginally to staphylococcal enterotoxin A (SEA) or phytohemagglutinin (PHA) in the absence of accessory cells. However, activation by the phorbol ester PMA in conjunction with either PHA or the calcium ionophore A23187 induces large amounts of IFN-gamma and IL-2. Histamine suppresses the lymphokine production in these pure T-cell cultures to a similar extent as in monocyte-containing cultures. Histamine is also shown to suppress DNA synthesis by purified T cells cultivated at a low cell density, eliminating any possible involvement of small numbers of contaminating accessory cells. In vitro preactivated T cells are shown to retain their capacity to respond to histamine when stimulated by PMA and A23187 or by mitogen in the presence of Raji cells. The conclusion that histamine acts directly on T cells and does not require accessory cells to induce suppression is further confirmed by the demonstration that IL-2 production by the human T-cell leukemia line Jurkat was significantly suppressed by histamine in a H-2 receptor-restricted manner.
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PMID:Histamine acts directly on human T cells to inhibit interleukin-2 and interferon-gamma production. 311 98


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