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)

In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by isolation perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) (4 mg). Bioactive TNF-alpha and interleukin 6 (IL-6) serum levels were measured serially. In the limb, TNF-alpha rapidly reached a plateau at 2 mu/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-alpha rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-alpha infusion in ILP results in extremely high levels of bioactive TNF-alpha in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.
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PMID:High serum levels of TNF-alpha after its administration for isolation perfusion of the limb. 129 42

A total of 22 patients with metastatic renal cell carcinoma or malignant melanoma were treated in a phase II study to assess the safety and efficacy of combination therapy of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). 3 x 10(6) U/m2/day recombinant human (rh)IL-2 was given in repetitive cycles by continuous 24-h infusion from day 1 to day 4; 6 x 10(6) U/m2/day rhIFN-alpha was given subcutaneously on days 1 and 4. There was one complete remission and two partial remissions in the renal cell carcinoma group and two partial remissions in the malignant melanoma group, giving an overall response rate of 24% in 21 evaluable patients with a median response duration of 5+ months. Toxicity was moderate, with hypotension, fever, chills, nausea, neurotoxicity, and dermatitis as prominent side effects. Measurement of circulating cytokine levels showed increased serum tumor necrosis factor-alpha (TNF), interferon-tau, and soluble interleukin-2 receptor levels during each cycle with a tendency to higher concentrations of TNF in responders as compared to nonresponders. With regard to therapeutic efficacy and tolerance, our approach might represent an alternative to the high-dose protocols and the labor- and cost-intensive strategies of adoptive immunotherapy.
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PMID:Combination of interleukin-2 and interferon-alpha in renal cell carcinoma and malignant melanoma: a phase II clinical trial. 130 89

In vitro studies and animal experiments showed the existence of a physiological immune response against tumors. Interleukin-2 was the first immunological agent which demonstrated an anti-tumor effect by activating immune effectors. In vitro IL2 may generate Lymphokine Activated Killer (LAK) cells from peripheral blood lymphocytes or Tumor Infiltrating Lymphocytes (TIL) expanded from tumor. In melanoma and renal cell carcinoma, IL2 alone or associated with LAK cells or TIL, mediated clinical responses. However, their clinical efficacy was associated with some toxicity related to a capillary leak syndrome. This implies an improvement in the selection of patients and in the understanding of IL2 action. Future directions in immunotherapy included combination IL2 with other cytokines or monoclonal antibodies or chemotherapy. Lymphokine gene therapy is designed to introduce IL2 or other cytokine genes into tumor infiltrating lymphocytes or directly into tumors to reduce systemic toxicity and to achieve high local cytokine concentration. Animal models and the first human trials make this approach promising.
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PMID:Current status of interleukin-2 therapy in cancer. 130 61

The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and metastasis. It has been demonstrated that in human models, cytokines such as TNF, IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of cell adhesion molecules on endothelial cell surfaces. We and others have shown similar cytokine-induced endothelial adhesiveness for tumor cells in murine and human models. In contrast to the effect of those modulators, transforming growth factor-beta (TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of TGF-beta action remains unknown. Little is known about the effect of TGF-beta on tumor cell-endothelial interaction. In the present study, we demonstrate that TGF-beta inhibits basal and TNF-enhanced binding of murine P815 mastocytoma cells to murine microvascular endothelium (MME). The alterations in MME mediated by TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine B16 melanoma cells. The effect of TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to MME. The TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on protein synthesis because cycloheximide reverses the TGF-beta effect. TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of G proteins do not abolish TGF-beta action, protein kinase C and protein kinase A activators elicit an effect opposite to that of the factor, TGF-beta does not increase intracellular cAMP levels, and finally calcium-mobilizing agents do not mimic, but rather inhibit the effect of TGF-beta. However, TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to MME is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid which suggests that TGF-beta may elicit its effect by stimulating protein phosphatase activity.
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PMID:Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. 131 61

Oncostatin M (OSM) was initially identified as a polypeptide cytokine which inhibited the in vitro growth of cells from melanoma and other solid tumors. OSM shows significant similarities in primary amino acid sequence and predicted secondary structure to leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), granulocyte colony-stimulating factor (G-CSF), interleukin 6 (IL-6), and interleukin 11 (IL-11). Analysis of the genes encoding these proteins reveals a shared exon organization suggesting evolutionary descent from a common ancestral gene. Recent data indicates that OSM also shares a number of in vitro activities with other members of this cytokine family. The overlapping biological effects appear to be explained by the sharing of receptor subunits.
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PMID:Oncostatin M. 133 75

Recent investigations indicate that malignant melanoma cells can produce distinct cytokines. While differences in the production of single cytokines have been observed among different melanoma cell lines, the extent of variability in the production of single and multiple cytokines between individual melanoma cell lines has not been as thoroughly investigated. A heterogeneity in melanoma cell cytokine production could have important implications for the biology of this aggressive neoplasm since certain cytokines may act as autocrine growth factors or be potent modulators of host immune response to the developing tumor. The purpose of this study is to assess the cytokine production profile of two widely available human melanoma cell lines, A375 and G361. The A375 cell line constitutively expressed the mRNA for IL-1 alpha, IL-1 beta and PDGF-A, with increased expression of these cytokines after induction with PMA. GM-CSF mRNA was expressed by the A375 melanoma line only after induction with PMA. No IL-6 mRNA was detected in the A375 melanoma cell line. The cell culture supernatants from the A375 cells likewise contained a parallel increase in IL-1 activity as determined in the D10 bioassay and secreted GM-CSF and PDGF-AA as measured by ELISA. In contrast, the G361 cell line did not express IL-1, GM-CSF or PDGF-A mRNA (constitutively or after PMA induction) but expressed only IL-6 mRNA and secreted IL-6 activity after PMA induction. These results demonstrate a significant heterogeneity in the production of IL-1 alpha, IL-1 beta, IL-6, GM-CSF, and PDGF in two distinct melanoma cell lines. This study demonstrates that individual melanoma cell lines express and secrete multiple cytokines both constitutively and after stimulation with PMA. The immunodulating and mitogenic properties of these melanoma-derived cytokines may have implications in determining the biologic behavior of different malignant melanomas.
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PMID:Heterogeneity of cytokine production by human malignant melanoma cells. 134 59

Intercellular adhesion molecule-1 (ICAM-1) is involved in cell-cell interactions of leukocytes and parenchymal cells and thus plays an important role in immunologic and inflammatory reactions. The expression of ICAM-1 that is found on many different cells such as melanocytes and melanoma cells is induced by various cytokines, including interferon-gamma (IFN gamma), interleukin (IL)-1 and tumor necrosis factor alpha (TNF alpha). Because expression of ICAM-1 in melanoma was found to correlate with increased risk of metastasis, the regulation of ICAM-1 expression on human melanocytes and melanoma cells was investigated. Foreskin-derived melanocytes and melanoma cell lines (A375, G361) were incubated with different cytokines and ICAM-1 expression was evaluated by fluorescence-activated cell sorter. IFN gamma, IL-1, IL-7, TNF alpha, and TNF beta significantly upregulated ICAM-1 expression in a dose-dependent manner. Most interestingly, the cytokine IL-6, which does not influence adhesion-molecule expression on other cells, significantly upregulated melanocyte and melanoma cell ICAM-1 expression. This effect was dose dependent and could be blocked by an IL-6 antibody. Irradiation with ultraviolet (UVB) light did not influence constitutive ICAM-1 expression on melanoma cells and melanocytes, but suppressed cytokine-induced ICAM-1 expression when cells were harvested 16 h after irradiation. These findings were further confirmed by Northern blot analysis, showing a marked accumulation of ICAM-1 mRNA after cytokine treatment, which was reduced by irradiation with UVB light. However, when UVB-exposed melanoma cells were cultured for at least 48 h induction of ICAM-1 expression was observed. These data indicate that, similar to other cells, ICAM-1 expression on melanoma cells and melanocytes is regulated by cytokines and that UVB light affects ICAM-1 expression on melanocytic cells in a biphasic manner.
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PMID:Modulation of intercellular adhesion molecule-1 expression on human melanocytes and melanoma cells: evidence for a regulatory role of IL-6, IL-7, TNF beta, and UVB light. 134 55

We have studied the cytokine regulation of cell surface and soluble intercellular adhesion molecule 1 (ICAM-1) expression on the human melanoma cell line A375M. Unstimulated cells express ICAM-1 on their cell surface but do not secrete significant levels of soluble ICAM-1. Interleukin 1, interleukin 6, tumor necrosis factor, and gamma-interferon all increased cell surface expression of ICAM-1. Tumor necrosis factor, interleukin 1, and gamma-interferon also caused the release of soluble ICAM-1. The serum of melanoma patients has been reported to contain elevated levels of soluble ICAM-1; however, the source of this ICAM-1 is unclear. The serum from nude mice bearing s.c. human melanoma tumors was found to contain soluble human ICAM-1. ICAM-1 levels showed a positive correlation with tumor weight. The release of ICAM-1 from melanoma tumors, in response to host-derived cytokines, may have relevance to immune recognition of the tumor.
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PMID:Soluble intercellular adhesion molecule 1 is released by human melanoma cells and is associated with tumor growth in nude mice. 134 68

The potential role of intercellular adhesion molecule 1 (ICAM-1) in the biology of human melanoma cells has stimulated interest in the characterization of its modulation. The present study has shown that the differentiating agent retinoic acid (RA) up-regulates ICAM-1 expression by melanoma cells in a dose- and time-dependent fashion. The enhancement of ICAM-1 cell surface expression is paralleled by an increase in ICAM-1 mRNA. Therefore, ICAM-1 represents an additional gene which may be transcriptionally regulated by RA. The five melanoma cell lines tested displayed a differential susceptibility to the modulation of ICAM-1 expression by RA, since the cell line MeWo did not change in its ICAM-1 expression following incubation with RA. Nevertheless, RA-insensitive as well as RA-sensitive melanoma cell lines displayed a higher increase in ICAM-1 expression following incubation with RA and cytokines than following incubation with each of them. Analysis of the distribution in the melanoma cell lines of retinoic acid receptors (RARs) showed a relationship between susceptibility to a RA-mediated increase of ICAM-1 expression and RAR beta expression, suggesting that the latter receptor may play a role in the phenomenon. RAR alpha and RAR gamma were present in RA-sensitive and -insensitive melanoma cell lines, suggesting that they play a role in the enhancement by RA of cytokine-mediated up-regulation of ICAM-1 expression. The melanoma cell lines we have described may represent a useful system for investigating the role of RAR in the regulation of gene expression and the mechanism(s) which underlie this effect.
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PMID:Differential susceptibility of cultured human melanoma cell lines to enhancement by retinoic acid of intercellular adhesion molecule 1 expression. 135 9

A soluble form of the usually membrane-bound adhesion molecule ICAM-1 was detected in supernatants derived from human epidermal keratinocytes. Specifically, supernatants harvested from long-term cultured normal human keratinocytes, or from the spontaneously immortalized keratinocyte cell line HaCaT, did not contain significant amounts of sICAM-1, but shedding of sICAM-1 was found to be markedly induced upon stimulation of keratinocytes with rh IFN gamma. In contrast, cells from the two epidermoid carcinoma cell lines, KB and A431, constitutively shed significant amounts of sICAM-1 even without cytokine stimulation, and sICAM-1 contents in supernatants harvested from these cells were further increased upon stimulation of cells with rh IFN gamma. These studies indicate, that in addition to peripheral blood mononuclear cells and human melanoma cells, human epidermal keratinocytes constitute an important cellular source of sICAM-1. By binding to leukocyte LFA-1 molecules, keratinocyte-derived sICAM-1 may influence inflammatory responses in the skin. In addition, constitutive shedding of sICAM-1 by transformed human keratinocytes may represent a possible mechanism by which neoplastic keratinocytes escape from cytotoxicity.
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PMID:Human epidermal keratinocytes are a source of soluble ICAM-1 molecules. 136 53


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