Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant macrophage colony-stimulating factor (M-CSF) is a hemopoietic growth factor capable of modulating activities of both immature and mature monocytes. The effect of M-CSF on tumoricidal activity of alveolar macrophages and monocytes from nonsmoking normal volunteers was compared using [3H]thymidine-labeled human tumor cells (SK-MEL-28, melanoma) as targets. A dose-response study (500-5,000 U/ml) of recombinant M-CSF indicated that both alveolar macrophages and blood monocytes demonstrated peak cytotoxicity at 1,000 U/ml. Maximal activity occurred 72-96 h after exposure to 1,000 U/ml of M-CSF. To investigate the mechanisms involved in this cytotoxicity, tumor necrosis factor-alpha (TNF) and interleukin-1-beta (IL-1) were measured in supernatant fluids of 24 h M-CSF-treated cells. No significant increase in either cytokine was detected after M-CSF treatment of alveolar macrophages or monocytes. Superoxide anion production of alveolar macrophages was not enhanced by M-CSF. These data suggest that alveolar macrophages tumoricidal activity is induced by M-CSF and is not dependent on oxidative metabolism or secreted forms of IL-1 or TNF.
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PMID:Modulation of human alveolar macrophage tumoricidal activity by recombinant macrophage colony-stimulating factor. 215 55

It has long been known that complex interactions occur between tumors and normal host immune cells. The human melanoma cell line A375 has been used previously as an indicator cell for tumor cell cytotoxicity mediated by monocytes. During other studies on this tumor cell line, we noted that the conditioned media harvested from A375 cultures induced both the human monocytoid cell line U937 and human blood monocytes to release the cytokine tumor necrosis factor (TNF). We characterized this tumor factor which induced TNF release by monocytic cells. Purification was performed using ammonium sulfate precipitation, ion exchange (DEAE) chromatography, gel filtration, and reversed-phase high performance liquid chromatography. The factor copurified with granulocyte-macrophage colony-stimulating factor (GM-CSF). The purified material caused the release of TNF by U937 cells and stimulated formation of granulocyte-macrophage colonies in methyl cellulose. TNF release by U937 cells in response to A375-conditioned medium was inhibited by neutralizing antibodies to GM-CSF. The TNF-inducing activity in A375-conditioned medium was completely removed by an anti-GM-CSF affinity column. Western blotting using antibodies to GM-CSF confirmed a single Mr27,000 band in A375-conditioned medium. We found that recombinant human GM-CSF stimulated TNF production by the same cells as the tumor-conditioned medium. These data show that A375 human melanoma cells produce GM-CSF, which in turn causes TNF production by cells in the monocyte lineage. The combination of GM-CSF production by the tumor and TNF production by immune cells may influence not only tumor growth but also some of the paraneoplastic syndromes associated with malignancy such as hypercalcemia, cachexia and leukocytosis.
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PMID:Stimulation of tumor necrosis factor release from monocytic cells by the A375 human melanoma via granulocyte-macrophage colony-stimulating factor. 218 30

The use of interleukin 2-based immunotherapies for cancer has been associated with significant responses in tumor models in both mouse and humans. Further definition of the elements responsible for response is now possible. It appears that the response is associated with T-cell infiltration of the tumor, and transfer of tumor-infiltrating lymphocytes expanded in tissue culture with interleukin 2 is associated with significant antitumor effects. Further expansion of cultured human melanoma tumor-infiltrating lymphocytes with suppression of lymphokine-activated killer activity as well as the modulation of monocyte activity by interleukin 4 suggests that this cytokine may be clinically useful alone or in combination with interleukin 2. Other means of enhancing the activity of interleukin 2-based immunotherapy are suggested by the finding that tumor cell susceptibility to lysis by natural killer cells is depressed following treatment with interferon gamma and tumor necrosis factor, but susceptibility to lysis by tumor-infiltrating lymphocytes is markedly enhanced. Further development of these therapies will require innovative interpretation and application of findings related to the processing and presentation of human tumor antigens and the nature of tumor antigens and careful analysis of the T-cell receptor in antitumor effectors.
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PMID:Mechanisms of immunologic antitumor therapy: lessons from the laboratory and clinical applications. 219 Sep 52

Macrophages and cultured human monocytes can mediate efficient antibody-dependent cytotoxicity (ADCC) against human tumor cells using monoclonal antibodies (mAbs). The mechanism of this killing is usually assumed to involve secreted factors (reactive oxygen intermediates, tumor necrosis factor, or other cytotoxic factors) leading to target cell lysis. In this study, we present evidence that phagocytosis of intact target cells is the principal mechanism of antitumor cytotoxicity in our in vitro model of ADCC by cultured monocytes. Human monocytes cultured in recombinant human macrophage colony-stimulating factor ingested up to 100% of fluorochrome-labeled melanoma and neuroblastoma target cells, in the presence of an appropriate antitumor mAb. Electron microscopy demonstrated phagocytosis of intact tumor cells by cultured monocytes during ADCC. All of the radionuclide in radiolabeled target cells was taken up by monocytes during phagocytosis. By preventing the release of radioisotope tracers, phagocytosis thus prevents the detection of this very efficient form of cytotoxicity by most conventional assays.
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PMID:Phagocytosis of tumor cells by human monocytes cultured in recombinant macrophage colony-stimulating factor. 219 96

This study has examined the effect of the cytokine interleukin 1 (IL-1) on metastasis formation by the human melanoma A375M in nude mice. We have found that human recombinant IL-1 beta (a single injection greater than 0.01 micrograms per mouse i.v. given before tumor cells) induced an augmentation of experimental lung metastases from the A375M tumor cells in nude mice. This effect was rapidly induced and reversible within 24 h after IL-1 injection. A similar effect was induced by human recombinant IL-1 alpha and human recombinant tumor necrosis factor, but not by human recombinant interleukin 6. 5-[125I]odo-2'-deoxyuridine-radiolabeled A375M tumor cells injected i.v. remained at a higher level in the lungs of nude mice receiving IL-1 than in control mice. In addition, IL-1 injected 1 h, but not 24 h, after tumor cells enhanced lung colonization as well, thus suggesting an effect of IL-1 on the vascular transit of tumor cells. These findings may explain the observation of enhanced secondary localization of tumor cells at inflammatory sites and suggest that modulation of secondary spread should be carefully considered when assessing the ability of this cytokine to complement cytoreductive therapies.
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PMID:Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. 219 16

Newcastle disease virus (NDV) has been used to induce regression of tumors in human cancer patients. We recently demonstrated that human malignant melanoma cells resistant to the lytic effects of tumor necrosis factor-alpha (TNF-alpha) become susceptible after treatment with NDV. We examined the effects of a serine protease inhibitor, N-1-tosylamide-2-phenyl-ethyl-chloromethyl ketone (TPCK), on viral enhancement of TNF cytotoxicity. Virulent NDV (but neither heat- nor UV-inactivated NDV) induced a 100-fold increase in the sensitivity of murine fibroblast L929 cells to recombinant human TNF-alpha (rHuTNF-alpha), rHuTNF-beta, and recombinant murine TNF-alpha (rMuTNF-alpha). TPCK, which is an inhibitor of chymotrypsin-like proteases, blocked between 42% and 93% of the cytolytic activity of rMuTNF-alpha, rHuTNF-alpha, and rHuTNF-beta toward NDV-treated L929 cells. Similarly, TPCK abrogated 62% of the cytotoxicity of rMuTNF-alpha toward dactinomycin-treated L929 cells. In contrast, TPCK had no effect on WEHI 164 clone 13 cells, a murine fibrosarcoma cell line that is much more sensitive to the lytic effects of TNF and does not show enhanced sensitivity to TNF after treatment with either NDV or dactinomycin. These results suggest a role for a cellular protease in the mechanism by which some viruses sensitize tumor cells to the cytolytic activity of TNF.
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PMID:Serum protease inhibitor abrogation of Newcastle disease virus enhancement of cytolysis by recombinant tumor necrosis factors alpha and beta. 229 51

The purpose of this study was to determine whether the incubation of human blood monocytes with tumor necrosis factor (TNF) induces tumoricidal activity. Peripheral blood monocytes isolated by centrifugal elutriation from buffy coats of healthy donors were incubated with lipopolysaccharide (LPS), lipopeptide derived from Escherichia coli (CGP-31362), recombinant human interferon-gamma (rIFN-gamma) plus muramyl dipeptide (MDP) or recombinant human TNF for 24 hr. The human melanoma A375-M (highly sensitive to TNF), A375-P (moderately sensitive to TNF), and A375-R (resistant to TNF) cells were all lysed in vitro by monocytes activated with LPS, CGP-31362, or MDP plus rIFN-gamma. On the other hand, A375-M, but not A375-P or A375-R cells, were lysed by human monocytes incubated with rTNF. After incubation with rTNF, paraformaldehyde-fixed monocytes lysed A375-M cells. Monocytes incubated with LPS, CGP-31362, and MDP plus rIFN-gamma secreted a high level of IL-1 activity into the culture medium, but monocytes incubated with rTNF did not. The cytolytic activities of monocytes incubated with LPS, CGP-31362, and MDP plus rIFN-gamma were not affected by the presence of anti-TNF antiserum, whereas the lysis of A375-M cells by monocytes incubated with rTNF was completely abolished by the presence of anti-TNF antiserum. We conclude that exogenous TNF does not render blood monocytes tumoricidal, but rather that TNF bound to cell-surface receptors can produce lysis of TNF-sensitive cells by a "carryover" mechanism.
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PMID:The incubation of human blood monocytes with tumor necrosis factor-alpha leads to lysis of tumor necrosis factor-sensitive but not resistant tumor cells. 233 40

Human skin melanocytes and melanocytes cultured in vitro express GM3 ganglioside almost exclusively, whereas malignant melanomas express high levels of both GM3 and GD3. We now show that treatment of cultured melanocytes with tumor necrosis factor-alpha, particularly in the presence of tetradecanoylphorbol-13-acetate, results in a change in morphology from spindle-shaped to epithelioid and greatly enhanced expression of GD3 ganglioside. This effect is specific and no other ganglioside is affected, except that GM3 expression (which is already high) is also increased. In contrast, these agents did not enhance the already high expression of GD3 on melanoma cells. This result provides an example of the plasticity of glycolipid expression in mammalian cells and their susceptibility to the influence of biological agents.
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PMID:Tumor necrosis factor enhances GD3 ganglioside expression in cultured human melanocytes. 238 25

Highly purified interleukin 1 (IL 1) obtained from stimulated human monocytes appeared to be growth inhibitory and cytocidal for a human melanoma cell line, A375. Although IL 1 did not have an immediate cytolytic effect, with time in culture the growth of the target cells was irreversibly inhibited. The cells eventually lysed and decreased markedly in number; the IL 1 effect can therefore be said to be cytocidal. IL 1 activity could not be separated from the cytocidal activity by a variety of chromatography procedures by using conventional and high-performance liquid chromatography (HPLC). The A375 melanoma cell line was also sensitive to another human cytokine alpha-lymphotoxin (alpha-LT) derived from a human B cell line. IL 1 also appeared to be partially growth inhibitory and cytocidal for a LT-sensitive mouse fibroblast cell line, L929; but not for LT-resistant cells, including a subline of L929; a human epithelial carcinoma cell line, HeLa; a human osteosarcoma cell line, HOS; and a mouse SV40-transformed kidney cell line, TU5. However, the LT-sensitive mouse fibroblast cell line, L-M, was resistant to IL 1. Therefore, the cytocidal activity of IL 1 only partially overlapped the target cell selectivity of alpha-LT. Although natural IFN-alpha and recombinant IFN-beta were appreciably growth inhibitory for the A375 cell line, natural and recombinant IFN-alpha and recombinant IFN-beta and IFN-gamma exhibited little cytocidal activity. Purified IL 1 did not have any antiviral activity, and conversely, IFN and alpha-LT were not co-mitogenic for thymocytes. Furthermore, by ELISA and radioimmunoassays, antibodies against human alpha-LT, tumor necrosis factor, and IFN-gamma did not react with IL 1, indicating that IL 1 is antigenically distinct from these other cytokines. These in vitro results suggest that IL 1 may play a role in host defense against some tumors as a cytocidal factor.
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PMID:Human interleukin 1 is a cytocidal factor for several tumor cell lines. 241 93

Nucleoticidin and melanocidins A and B exhibited potent inhibitory activity against 5'-nucleotidases from rat liver membrane and snake venom. Nucleoticidin retarded growth of Sarcoma 180 solid tumor, and melanocidins A and B prolonged the survival period of mice bearing B16 melanoma. These inhibitors enhanced phagocytic activity, interleukin-1 production and superoxide-generating activity of murine peritoneal macrophages. The tumor necrosis factor was also induced by the inhibitors. These results suggested that 5'-nucleotidase inhibitors inhibit tumor growth by modification of the immune system.
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PMID:Effect of 5'-nucleotidase inhibitors on mouse immune system and experimental murine tumors. 242 33


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