Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate acute effects of various doses of the cytokines IFN-alpha, IFN-gamma, Interleukin 2 and tumor necrosis factor alpha on white blood cell differential counts. Before initiation of phase II trials, a dose-determination phase was performed, where three different dose levels of each cytokine were applied as a single dose. White blood cell differential counts were assessed immediately before and 2, 12, 24, 48 and 168 h after injection. Patients enrolled suffered from metastatic cancer or chronic active hepatitis. In addition, IFN-alpha was administered to five healthy volunteers. Results indicate that cytokines cause rapid and transient changes in the numbers of leukocyte subsets. Hematologic changes were cell-type- and cytokine-specific: transient lymphopenia was observed after administration of all four cytokines, reaching a nadir 12 to 24 h after subcutaneous injection. Administration of TNF-alpha and IFN-gamma also caused transient monocytopenia. Neutrophilia developed after administration of Interleukin 2, IFN-alpha and TNF-alpha. We conclude that cytokines play a key role in the regulation of peripheral blood cell traffic by their capacity to influence homing patterns of peripheral blood leukocytes.
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PMID:Acute hematologic effects of interferon alpha, interferon gamma, tumor necrosis factor alpha and interleukin 2. 190 9

A variety of biologic and synthetic agents protect BALB/c mice against experimental M109 micrometastases. We have presented evidence that eradication of these metastases is mediated by the activation of host macrophages to the tumoricidal state. We now present evidence that injection of H22, a neutralizing hamster IgG monoclonal antibody to murine interferon-gamma (IFN-gamma; macrophage activating factor), 2 days prior to i.v. tumor inoculation markedly increases the metastatic capacity of M109 lung carcinoma cells. Therefore, we tested several cytokines that induce or mediate macrophage-mediated cytotoxicity, including IFN-gamma, tumor necrosis factor-alpha, and interleukin-1 beta (IL-1 beta), for their ability to inhibit the development of experimental M109 lung metastases. Intraperitoneal treatment with recombinant murine (rMu) IFN-gamma (greater than or equal to 10,000 units/mouse) or recombinant murine TNF-alpha (greater than or equal to 10,000 units/mouse) produced greater than 60% inhibition of metastasis formation. Optimal therapy was observed when cytokines were administered 2 days prior to i.v. tumor cell inoculation. Neither IFN-gamma nor TNF-alpha inhibited colony formation of M109 cells in vitro, suggesting a host-mediated mechanism for antitumor activity. Peritoneal macrophages were primed for tumor cytotoxicity by treatment with either IFN-gamma or TNF-alpha. Intraperitoneal treatment with recombinant human IL-1 beta (1 X 10(5) units) lacked antimetastatic activity. The results further support the role of activated macrophages in the destruction of M109 micrometastases.
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PMID:Protective activity of recombinant murine tumor necrosis factor-alpha and interferon-gamma against experimental murine lung carcinoma metastases. 211 56

In vitro macrophage- or TNF-alpha-mediated selection procedures on 3LL tumor cells have led to the selection of 3LL variants manifesting a highly reduced sensitivity towards the cytotoxic effects of both TNF-alpha and tumoricidal macrophages, while retaining the parental sensitivity to the cytolytic activity of (i) H2O2, (ii) macrophage-ADCC reactions and (iii) NK cells. A correlation was observed between the TNF-alpha binding capacity of the 3LL cell lines and their susceptibility towards macrophage- and TNF-alpha-mediated cytotoxicity, indicating that macrophage and TNF-alpha sensitivity may partially be regulated at the TNF-alpha receptor level. Further, the selected 3LL variants are gene-regulatory variants rather than cellular mutants, as upregulation of the TNF-alpha receptor by interferon-gamma (IFN-gamma) or 5'-azacytidine treatment resulted in an increased vulnerability of the selected 3LL variants to the killing activity of macrophages and TNF-alpha. The resistance of the 3LL variants to macrophage- and TNF-alpha-mediated cytotoxicity in vitro was reflected by a higher tumorigenic and metastatic potential in vivo. Therefore, the generation of TNF-alpha- and macrophage-resistant variants through immunoselection may contribute to the basic mechanisms of tumor progression and metastasis.
Clin Exp Metastasis
PMID:TNF-alpha mediated selection of macrophage-resistant gene-regulatory tumor variants. 247 62

This investigation was undertaken in order to assess both the preventive and antiproliferative effects of tumor necrosis factor (TNF) in a hepatic metastasis model, by means of inoculation of mouse colon-26 tumor cells into the portal vein via the superior mesenteric vein in male CDF1 mice, aged 5 weeks. Continuous 10-day administration of natural human TNF-alpha (nHuTNF-alpha) following the tumor cell inoculation caused no reduction but rather an increase in the number of hepatic metastases. However, pretreatment with this preparation daily for 10 days before the inoculation caused a remarkable decrease in the number of hepatic metastases. This prophylactic effect was reversed by the intravenous administration of anti-asialo GM1 antibody 24 h before the inoculation. The result of immunoperoxidase staining of liver specimens suggested that organ-associated natural killer cells might play a role in the metastatic inhibition. An apparent antiproliferative effect on metastatic liver tumors was also recognized following injection of nHuTNF-alpha from the 10th day after the inoculation. Thus, TNF appears to have important effects upon the host immune system, acting against liver metastases.
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PMID:Preventive and antiproliferative effects of tumor necrosis factor against experimental hepatic metastases of mouse colon-26 tumor. 250 Dec 53

Tumor necrosis factor (TNF-alpha) was compared to immune interferon (IFN-gamma) for its ability to modulate the expression and shedding of HLA antigens, of intercellular adhesion molecule I (ICAM I) and of high-molecular-weight melanoma-associated antigen (HMW MAA) by a panel of melanoma cell lines. The latter included the melanoma cell line MeWo and its metastatic variant MeM 50-10, which display differential susceptibility to modulation of HLA class-II antigens by IFN-gamma and the cell lines SK-MEL-93-DX-2 and SK-MEL-93-DX-3, which originated from anatomically distinct metastases in patient DX. TNF-alpha enhanced the expression of HLA class-I antigens on all 7 melanoma cell lines tested, although to a lower extent than IFN-gamma and the combination of IFN-gamma and TNF-alpha. TNF-alpha displayed a differential effect on the expression of HLA class-II antigens by the 7 melanoma cell lines: it enhanced it on 3 out of the 4 cell lines with constitutive expression of HLA class-II antigens and induced them on 1 of 3 cell lines without detectable expression of these antigens. The effects of IFN-gamma were different since it enhanced HLA class-II antigens on the 4 cell lines with constitutive expression of these antigens and induced them on 2 out of the remaining 3 lines. Interestingly, both TNF-alpha and IFN-gamma enhanced the expression of HLA class-II antigens by SK-MEL-93-DX-3 cells. On the other hand only TNF-alpha induced the expression of HLA class-II antigens by MeWo cells and only IFN-gamma induced such expression by MeM 50-10 cells and by SK-MEL-93-DX-2 cells. The effect of the combination of TNF-alpha and IFN-gamma was similar to that of the individual cytokines. Both TNF-alpha and IFN-gamma displayed a differential effect on the expression of the gene products of the HLA-D region by the melanoma cell lines. Northern blot analysis with HLA-DR beta-, DQ beta- and DP beta-specific probes suggests that the modulation of HLA class-II antigens by both cytokines reflects transcriptional and post-transcriptional events. TNF-alpha enhanced the expression of ICAM-I on all the melanoma cell lines, although to a lower extent than IFN-gamma and the combination of IFN-gamma and TNF-alpha. Lastly, neither TNF-alpha nor IFN-gamma displayed a marked effect on the expression of HMW-MAA by the melanoma cell lines tested.
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PMID:Differential modulation by tumor necrosis factor and immune interferon of HLA class-II antigens expressed by melanoma cells. 250 38

Metastasis is one of the great characteristics of malignant tumors. On the basis of our data, we reported here the immunotherapy for hematogenous metastasis. A randomized controlled study of preoperative transendoscopic intratumoral injection of BRM into gastro-intestinal cancer, which was performed in our Department, revealed a decreasing tendency of distant metastases in lymph node for the injection group, suggesting the disappearance of micro-metastasis due to the injection, namely, systemic immuno-enhancement due to the local effect, leading to diminution of hematogenous metastasis. Next, a mixture of natural human TNF-alpha (nHuTNF-alpha) and natural human IFn-alpha(nHuIFN-alpha), the so-called OH-1, was described. The results of a clinical study dealing with the antitumor effect on advanced and recurrent malignant tumors made it clear that all of the effective results (72 cases) such as CR and PR were obtained by an administration schedule with a maintenance dose of more than 200 X 10(4)U; rate of efficacy was 19.4% (4 cases of CR, 10 of PR and 4 of MR). By disease, breast cancer, renal cancer and liver cancer evidenced the most remarkable effects. Examination of the antitumor effect by metastatic organ revealed the effectiveness on hematogenous metastasic tumor of lung, bone and liver, though dependent upon underlying diseases. Finally, being based on our in vitro and in vivo results, we discussed the role of these immunotherapies for metastatic tumors.
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PMID:[The metastatic tumor and immunotherapy]. 273 24

We screened a panel of 8 primary and 21 metastatic melanoma cell lines for constitutive secretion of cytokines. Melanomas expressed bioactivity for TGF-beta (8/25 lines) and IFN (7/12), but not IL-2. Immunoassays detected IL-1 alpha (4/25), IL-1 beta (12/25), IL-6 (13/29), IL-8 (29/29), TGF-beta 2 (5/12) and GM-CSF (11/29), but not IL-3, IL-4, TNF-alpha, or IFN-gamma. There was no preferential association of cytokine production with cells cultured from primary versus metastatic disease, and only IL-8 was produced by all lines tested. These data demonstrate that cultured melanomas produce a variety of cytokines which are potentially capable of influencing tumor growth in vivo.
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PMID:Production of multiple cytokines by cultured human melanomas. 751 80

Most tumors grow progressively and overwhelm the host. The rare but documented cases of spontaneous regression of primary tumors are indicative of the potential of tumor-bearing hosts to develop a significant antitumor response. Because most tumors grow progressively in the host, it is not surprising that the majority of studies have focused on T lymphocytes that infiltrate these tumors. Although these studies have generated significant and useful information during the period of tumor growth, they can only speculate on the mechanisms that are involved in tumor rejection. We have used a well developed sponge model of concomitant tumor immunity that allows us to compare the immunologic events that occur during tumor progression vs rejection. In this model, an animal harboring a primary EMT6 mammary tumor is challenged with a secondary tumor implant through a pre-implanted gelatin sponge. During the manifestation of concomitant tumor immunity, the secondary tumor is rejected and the effector cells mediating the response are retained within the sponge matrix. Using this model we analyzed the TCR usage, cytotoxic activity of lymphocytes, and cytokine production at both tumor sites. The data revealed that tumor-rejecting lymphocytes isolated from the site of secondary tumor implant were cytotoxic toward EMT6 cells, whereas tumor-infiltrating lymphocytes isolated from the progressing primary tumor were not. Interestingly, the TCR-V beta repertoire of the tumor-infiltrating lymphocytes and tumor-rejecting lymphocytes were identical with V beta 1 and V beta 8 being predominant at both sites. Furthermore, the rejection site showed higher gene expression of IFN-gamma, TNF-alpha, and IL-10 whereas TGF-beta expression was slightly higher in the progressing tumors. These findings suggest that the disparate effector functions observed during tumor progression vs rejection are not caused by different T cell phenotypes but may be due instead to influences exerted by cytokines produced at the tumor sites.
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PMID:T lymphocytes infiltrating sites of tumor rejection and progression display identical V beta usage but different cytotoxic activities. 770 35

The molecular mechanisms of tumor invasion and metastasis are yet to be fully elucidated. A potential tumor-metastasis-suppressor gene nm23 has been described in certain rodent and human tumors. In the present study, we examined the potential anti-invasive and anti-metastatic effect of nm23 gene in B16F10 cells, a malignant murine melanoma cell line. Transfection of nm23 gene into B16F10 melanoma cells resulted in significant suppression of the invasiveness and metastatic ability of melanoma cells and significantly enhanced the survival of tumor-bearing mice. B16F10 melanoma cells transfected with nm23 produced significantly less soluble ICAM-I and were more susceptible to LAK-cell-mediated cytotoxicity. Co-culture of B16F10 melanoma cells with IL-2 had no effect on nm23 expression, whereas treatment with PGE2, TNF-alpha and IFN-gamma resulted in down-regulation of nm23 expression. Concomitantly, in vivo treatment with TNF-alpha or IFN-gamma in experimental mice increased pulmonary metastases and lowered the overall survival period, as compared with IL-2 treatment alone. These results provide evidence that nm23, in addition to its anti-metastatic function, could also be involved in modulating tumor-target-structure expression, in down-regulating invasive potential and in production of soluble intracellular adhesion molecules. The down-regulation of nm23 by TNF-alpha, IFN-gamma and particularly by PGE2 warrants re-examination of current immunotherapeutic protocols and of the role played by PGE2 in tumor progression.
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PMID:Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. 782 17

The 92-kD type IV collagenase is a member of the metalloproteinase family which degrades type IV collagen, a major component of basement membrane and is involved in tumor invasion and metastasis. The promoter and adjacent regulatory sequences of the 92-kD type IV collagenase have been identified previously and three cis-acting elements homologous to the binding sites for AP-1, NF-KB and SP-1 proteins contributed to induction of the promoter activity by 12-O-tetradecanoylphorbol 13-acetate (TPA) and tumor necrosis factor (TNF-alpha) in HT1080 cells. To date, no direct correlation between promoter activity and expression of the 92-kD type IV collagenase has been reported in normal or cancer cells. In this study, the effects of the transcriptional stimulation of the 92-kD type IV collagenase gene on the expression of the enzyme in human A2058 melanoma cells was analyzed by zymography experiments. Quantitative immunoblots using a monoclonal antibody that recognized specifically and exclusively the 92-kD type IV collagenase, confirmed that the 92-kD gelatinase was 92-kD type IV collagenase. Stimulation of the promoter activity resulted in increased gelatinase activity in the culture medium of A2058 cells. A direct correlation between TPA- and TNF-alpha-mediated promoter stimulation of the 92-kD type IV collagenase gene and its expression was also demonstrated in the human fibrosarcoma HT1080 cells. Interleukin-1 alpha failed to induce 92-kD gene promoter activity and type IV collagenase expression in melanoma and fibrosarcoma cell lines. Our data demonstrated that TPA- and TNF-alpha-induced 92-kD type IV collagenase promoter stimulation leads to a proportional increase of enzyme expression and secretion and thus could contribute to the activation of the invasive phenotype.
Invasion Metastasis 1993
PMID:Stimulation of the 92-kD type IV collagenase promoter and enzyme expression in human melanoma cells. 786 Feb 22


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