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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In summary, molecular biology and advances in biochemical and biological techniques have led to the rapid characterization of a large number of cytokines. These are released in response to injury or invasion of the body and regulate the growth and function of a broad variety of cell types. Many cytokines are now in clinical trials and show promise in modulating the defence and repair responses of the body. The direct application of these cytokines to the killing of tumor cells remains problematic. However, it does seem likely that the use of these substances in a para-physiological mode i.e. in activating defence mechanisms and in particular stimulating hemopoetins may be a very important adjunct to more conventional means of tumor therapy such as chemotherapy or radiotherapy. The hemopoietic growth factors show particular promise here, although other substances such as IL-1 or IL-6 may find similar applications. In the future more information on the direct role of cytokines in the development of particular tumors may lead to the development and use of cytokine antagonists with effects directed at tumor cells or their environment.
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PMID:Tumor treatment and cytokines. 223 65

The effect of mitogens and/or recombinant B-cell growth factors (M/GFs) on the in vitro growth of hairy cells was examined. Tumor cells were isolated from the spleens of four patients with hairy cell leukemia (HCL) by Ficoll-Hypaque sedimentation and E-rosetting. Enrichment for tumor cells was confirmed with intracytoplasmic immunoglobulin (Ig) staining, tartrate resistant acid phosphatase (TRAP) staining, and staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, and monocytoid antigens (Ags) in indirect immunofluorescence assays. Tumor cells were B1(CD20)+ B2(CD21)- B4(CD19)+ IL-2R(CD25)+ PCA-1 +/- TRAP+. HCLs neither synthesized DNA nor secreted Ig in response to culture with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, or IL-6. However, a proliferative response (stimulation index greater than or equal to 3.0) without Ig secretion was triggered in HCLs by mitogens or combinations of GFs. Specifically, DNA synthesis was induced at 3 days in three of four HCL samples cultured with Staphylococcus aureus Cowan A (SAC) or the combination of phorbol ester (TPA) and the calcium ionophore A 23187 (Ca2+); DNA synthesis was triggered later (day 7) by tumor necrosis factor (TNF) or by IL-4 and IL-5. In contrast, the fourth patient, a nonresponder to SAC or TPA/Ca2+, demonstrated increased DNA synthesis at day 3 when cocultured with IL-4 and IL-5. Both autoradiography and staining with antibromodeoxyuridine (BrdU) MoAb conjugated to fluorescein confirmed DNA synthesis by only a minority (5% to 23%) of tumor cells within each patient. Dual staining confirmed that responsive cells were both BrdU+ and TRAP+. DNA synthesis induced by TPA/Ca2+ was blocked specifically by anti-IL-6 Ab; in contrast, the HCL proliferative response to SAC, TNF, or IL-4 and IL-5 was not inhibited by anti-IL-6 Ab. alpha-Interferon inhibited the response to TPA/Ca2+, TNF, or IL-4 and IL-5 without any effect on response to SAC. Finally, peroxidase-antiperoxidase staining demonstrated that HCLs are induced by TPA/Ca2+, but not by SAC, to produce intracytoplasmic IL-6. These data demonstrate IL-4, IL-5, and IL-6 mediated DNA synthesis by HCLs in vitro and suggest a possible in vivo role for these growth factors in the pathophysiology of HCL.
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PMID:Response patterns of hairy cell leukemia to B-cell mitogens and growth factors. 224 29

Cytokines are (glyco)proteins that are synthesized and secreted by various cells, which bind to specific receptors on target cells and which regulate activation, proliferation, and differentiation of immune as well as non-immune cells. Keratinocytes upon injury release interleukin (IL)-1, IL-6, IL-8, colony-stimulating factors, and tumor-necrosis factor, as well as growth and suppressor factors. There is also strong evidence for a network of interacting cytokines, which has been only partially characterized so far, maintaining a proper balance. However, excessive or insufficient production of these mediators may contribute to certain disease states, particularly those with infectious and autoimmune genesis. Therefore the understanding of cytokine interactions may be helpful in elucidating the pathomechanisms of such diseases. Moreover, certain cytokines, as well as their analogues and antagonists, may prove to be of therapeutic value.
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PMID:Evidence for an epidermal cytokine network. 225 24

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo, recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P less than .01). Furthermore, GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact, this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line), rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL-6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells, nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients, it is possible that GM-CSF, produced locally by the tumoral environment, enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.
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PMID:Granulocyte-macrophage colony-stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells. 207 93

IL-6 possesses multiple biologic activities that affect a broad range of cells including those directly involved in immune responses as well as cells important in the systemic response to infection or trauma. We now show that purified human rIL-6, when administered alone at relatively high doses that are comparable to therapeutic levels of IL-2, mediated substantial reductions in the number of pulmonary and hepatic micrometastases from four distinct syngeneic tumors. Unlike IL-2, IL-6 injections resulted in neither observable toxicity nor death of the treated mice at the dose regimens used. Host immunosuppression by sublethal total-body irradiation before the initiation of therapy prevented the IL-6 antitumor effect, thus suggesting that IL-6 acted through a radiosensitive host component rather than directly on the tumor itself. Moreover, the systemic administration of relatively low doses of IL-6 in combination with subtherapeutic doses of TNF to mice bearing an established weakly immunogenic, syngeneic tumor at a subcutaneous site resulted in marked tumor regression and cure rates. These studies represent the first demonstration of tumor regression mediated by recombinant IL-6 in vivo.
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PMID:Antitumor activity of recombinant interleukin 6 in mice. 230 30

Plasma cell myeloma is a more complex neoplasm than suggested by the relative uniformity of its dominant plasma cells, which represent the terminal stage of normal B-cell differentiation. Phenotypic, molecular, and cellular genetic data favor the presence of a myeloma stem cell early in hematopoietic development so that, as in chronic myelogenous leukemia (CML), a far distance exists between the primordial malignant cell that was the target of malignant transformation and the dominant clinical phenotype. Traces of pre-B, myeloid, and T cells are coexpressed with the mature B-cell phenotype, an occurrence unknown in normal B-cell differentiation. Analogous to CML, disease progression is marked by disease dedifferentiation, occasionally with cessation of myeloma protein production and development instead of extramedullary lymphomalike features with high LDH or myelodysplasia/acute myelogenous leukemia (AML) syndromes. The prognostic importance of serum LDH levels even in newly diagnosed myeloma suggests the early presence of tumor cells with "LDH phenotype," which, as a result of drug resistance and proliferative advantage, expand preferentially during disease progression. Further characterization of these cells may provide important clues about the ontogeny of multiple myeloma. Myeloma cells express many receptors for different biological signals that might be exploitable for therapy with immunotoxins or radioisotopes. Plasma cells and their precursors also produce a variety of cytokines, some of which have putatively autostimulatory functions (eg, IL-1, IL-5, IL-6) and/or are related to disease manifestations (eg, IL-1 and TNF-beta as OAF). The wealth of cellular expression by plasma cells provides clues for understanding the mechanisms of gene activation and the nature of abnormal growth and differentiation. The accuracy of prognostically relevant staging systems has been refined with the use of new quantitative parameters that reflect tumor mass (ie, serum B2M levels) and biology. Further studies of cellular and molecular biology (ie, CAL-LA, H-ras) may reveal those tumor cell features that define clinical entities, response to therapy, and long-term prognosis. The lack of a major advance in prognosis despite the use of more drugs and more intensive regimens justifies the continued use of standard melphalan-prednisone for patients with a highly favorable prognosis, for the very aged, and for those with a short life expectancy due to other major medical problems. However, a radical departure from standard practice is required to improve the prognosis for younger patients with poor risk features.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Plasma cell myeloma--new biological insights and advances in therapy. 246 90

The acute phase cytokines: interleukin 1, tumor necrosis factor alpha (cachectin) and beta (lymphotoxin), hepatocyte stimulating factor and several interferons, all belong to the family of endotoxin-inducible, low molecular weight proteins. Their synthesis in macrophages, fibroblasts, lymphocytes, epithelial and some tumor cells is enhanced by the same cytokines, often in the autocrine manner, and suppressed by dexamethasone. The principal hepatocyte stimulating factor (HSF) regulating synthesis of acute phase proteins is probably identical with IFN-beta 2/BSF-2/IL-6, but other inflammatory cytokines (IL-1, TNF alpha, IFN-gamma) are able to induce distinct sets of acute phase proteins, or to modulate the final response pattern. The effect of hrIFN-gamma on production of acute phase proteins by human hepatoma Hep G2 cells is discussed in detail. It is concluded that the cascades of inflammatory cytokines in different tissues represent amplification and regulatory pathways controlling the development of acute phase response in vivo.
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PMID:The cascade of inflammatory cytokines regulating synthesis of acute phase proteins. 248 65

We investigated the capacity of several recombinant cytokines to induce IL-6 in vivo in both normal and tumor-bearing (TB) mice. Intravenous administration of human rhTNF-alpha, rhIL-1, rhIL-2, rhIFN-alpha A/D, and rmIFN-gamma were all capable of inducing circulating IL-6. rhTNF-alpha administration caused the greatest induction of IL-6. TB animals consistently produced more IL-6 in response to rhTNF-alpha than did normal mice (2 h after 4 micrograms rhTNF-alpha, TB = 24,100 HGF U/ml, non-TB = 3600 HGF U/ml of IL-6). A single daily i.v. dose of rhTNF-alpha (4 micrograms/mouse/day) for 5 days led to decreased IL-6 induction in TB animals by day 3 of treatment (peak levels of IL-6, day 1 = 72,800 HGF U/ml, day 3 = 23,400 HGF U/ml, day 5 = 26,400 HGF U/ml). rhIL-1 administration also resulted in considerable IL-6 production, although peak values were less than those resulting from administration of rhTNF-alpha. Administration of rhIL-1 induced similar IL-6 levels (TB = 10,025 and non-TB = 10,600 HGF U/ml) in TB and normal mice. Single high doses of rhIL-2, rhIFN-alpha A/D, and rmIFN-gamma induced lower but consistent levels of circulating IL-6 in mice with and without tumor. In addition, the sera of untreated TB mice contained levels of IL-6 which paralleled the extent of tumor burden (serum IL-6 in day 30 MCA 106 TB mice = 420 HGF U/ml). The detection of de novo IL-6 was also confirmed in animals bearing tumors of different histologies (the MCA 102 sarcoma, MCA 38 adenocarcinoma, and B16 melanoma). At no time was IL-6 measurable in the sera of untreated normal mice. The identification of IL-6 was verified by neutralization studies using specific antimurine IL-6 antibody. Although the exact role of IL-6 in TB animals remains to be elucidated, its known pleotrophic immune and metabolic effects may be important in the host response to malignancy.
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PMID:In vivo induction of IL-6 by administration of exogenous cytokines and detection of de novo serum levels of IL-6 in tumor-bearing mice. 249 26

When cultured with IL-2, human lymphoid cells acquire the ability to lyse various NK-resistant tumor targets. Due to their anti-tumor cytolytic effect, clinical trials with IL-2 alone or IL-2 + IL-2-activated killer (IAK) lymphocytes have been undertaken. However, infusion of therapeutically effective doses of IL-2 is associated with the development of systemic toxicity characterized by exaggerated endothelial permeability, also known as vascular leak syndrome. The present study was designed to examine the effects of IAK cells and their secreted products on vascular endothelial permeability by using an in vitro endothelial permeability model in which the flux of FITC-albumin across endothelial cell (EC) monolayers was measured. When endothelial monolayers were exposed to IAK cells for 2 h, significant increases in the transendothelial permeability to albumin were observed. Exposure of EC to lymphocytes cultured in the absence of IL-2 did not induce significant alteration in the endothelial permeability. In addition, neither culture supernatants of IAK cells nor purified recombinant cytokines, including IL-1 beta, IL-2, IL-3, IL-4, IL-6, TNF-alpha, GM-CSF, M-CSF, and IFN-gamma, had any effect on endothelial permeability in this model. Prior activation of EC with TNF-alpha did not alter the increased permeability induced by IAK cells or lack of it by nonactivated lymphocytes. Dexamethasone treatment of IAK cells abolished their anti-tumor cytolytic effect but only partially inhibited their ability to induce increased endothelial permeability. Pretreatment of IAK cells with mAb directed at the CD11a/CD18 (LFA-1) adhesion complex, and that of EC with mAb directed at the ICAM-1 molecule, inhibited the IAK cell-induced increase in endothelial permeability. These results demonstrate that direct cell-to-cell contact between IAK cells and EC is necessary and sufficient to cause increased endothelial permeability in this model system, and may therefore be an important factor contributing to the development of the vascular leak syndrome observed clinically.
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PMID:IL-2-activated human killer lymphocytes but not their secreted products mediate increase in albumin flux across cultured endothelial monolayers. Implications for vascular leak syndrome. 252 65

Our study was designed to investigate the production of interleukin-1 (IL-1) and IL-6 in tumor-associated macrophages (TAM) isolated from ascites (18 cases) or solid (7 cases) human ovarian carcinoma. These are pleiotropic monokines which, in addition to affecting proliferation and differentiation of lymphocytes, act on various targets, including vascular cells and liver, and may therefore be involved in the pathogenesis of certain manifestations of malignancy. IL-1 was measured by the thymocyte co-stimulator assay, under conditions in which IL-6 was inactive, and, in 8 cases, by radioimmunoassay (RIA). IL-6 was measured as hybridoma growth factor (HGF) on the 7TD1 cell line. TAM did not release appreciable levels of IL-1 spontaneously and, upon LPS stimulation, were poor producers of this monokine compared to blood monocytes. In contrast, TAM supernatants contained a high level of HGF in the absence of deliberate stimulation, and exposure to LPS either did not affect or further augmented production of this monokine. HGF activity of TAM supernatants was completely blocked by anti-IL-6 antibodies. Ascites fluid from 8 ovarian-carcinoma patients contained high levels of HGF activity, blocked by anti-IL-6 antibodies. Thus, TAM exhibit a dissociation in their capacity to release the functionally related monokines IL-1 and IL-6. IL-6 produced by TAM may account for the elevation of liver-derived acute-phase proteins associated with malignancy.
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PMID:IL-1 and IL-6 release by tumor-associated macrophages from human ovarian carcinoma. 258 59


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