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)

The Surgery Branch of the National Cancer Institute has initiated several clinical trials involving the use of high-dose TNF in isolated limb perfusions. A phase III trial compares the three drug combination of TNF, interferon-gamma (IFN-gamma) and melphalan with a standard melphalan-alone perfusion in a prospective randomized trial. Another protocol escalates the dose of TNF in the perfusate to define the maximally tolerated dose that can be administered in this regional manner. A third protocol adds systemic high-dose interleukin-2 postoperatively to a TNF, IFN, and melphalan limb perfusion for patients with stage IV melanoma with the bulk of the disease in the extremity. This brief review highlights the rationale and study design of these TNF limb perfusion protocols.
Melanoma Res 1994 Mar
PMID:The use of tumour necrosis factor (TNF) in isolated perfusion: results and side effects. The NCI results. 803 92

Peptides from 10 to 22 amino acids containing sequences encompassed by Staphylococcus aureus protein A were synthesized. Some of these peptides, when present in cultures of lymphomononuclear cells from healthy donors or from cancer patients (melanoma, breast carcinoma, non-Hodgkin lymphoma and renal cell carcinoma) promoted: (i) changes in the phenotype of the lymphomononuclear population, (ii) stimulation of monocytes (release of IL-1 and TNF-alpha), and (iii) an increase in cytotoxicity against K562, Daudi and HT-29 cells. Isolated monocytes responded also to those peptides with a release of IL-1 and TNF alpha and an increase of cytotoxicity against HT-29 cells. It was found that the active peptides had the following structural pattern: a length of at least 15 amino-acid residues with a proline at position 6, valine, leucine, isoleucine, glycine, alanine or lysine at position 2, and glutamic or aspartic acid at position 11. Replacement of Pro at position 6 with any other residue turned the peptide inactive. Replacement of residues at positions 2 and 11 with amino-acid residues other than those required for activity resulted in compounds with a marked decrease in the immunomodulating properties described, or lacking these properties altogether.
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PMID:Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A. 814 92

We have analyzed the immunomodulatory effect of human melanoma gangliosides bound to serum lipoprotein fractions on normal human immune-competent cells in vitro. Total melanoma gangliosides in micelles inhibited proliferation of peripheral blood mononuclear cells stimulated by various mitogens, modulated lymphocyte surface molecules CD2, CD3, CD4, CD5 and CD8 and inhibited the production of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha) and IL-6 by stimulated adherent cells. Most of these effects were abrogated in the presence of serum. Purified serum lipoprotein fractions were tested for their ability to allow or inhibit the immunomodulatory effects of gangliosides. Melanoma gangliosides bound to very-low-density lipoproteins (VLDL) were shown to be as potent modulators of the immune response in vitro as when they were presented to cells in the form of micelles. Gangliosides bound to low-density lipoproteins were less active and gangliosides bound to high-density lipoproteins or the lipoprotein-free fraction had no immunomodulatory effects. Given the fact that gangliosides are predominantly bound to lipoproteins in serum, we conclude that lipoproteins are important determinants of the immunomodulating potential of tumor gangliosides, and that the immunomodulatory effects of melanoma gangliosides observed in vitro may also occur in vivo.
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PMID:Inhibition of immune cell proliferation and cytokine production by lipoprotein-bound gangliosides. 816 13

Transfection of BL6-8 (H-2Kb-,H-2Db+) and BL6-2 (H-2Kb-,H-2Db-) melanoma clones with H-2Kb or H-2Kd gene resulted in a stable augmentation of their sensitivity to lysis by NK cells or TNF-alpha that was associated with alterations of various phenotypic properties such as loss of endogenous A- and C-type retrovirus production and expression of melanoma-associated antigen and appearance of cell surface carbohydrates reacting with soybean agglutinin (SBA) and Grifonia simplicifolia 1-B4 (GS1B4) lectins. In contrast, transfection of the same clones with H-2Dd or H-2Ld gene did not reverse their resistance to NK cell- and TNF-mediated cytotoxicity and did not affect the phenotype of melanoma cells. These data suggest that the effect of H-2K gene on NK/TNF sensitivity of BL6 cells is indirect and it is closely associated with H-2K-induced phenotypic changes in these cells. To examine the possible role of the observed alterations of cell surface carbohydrates in augmentation of sensitivity of BL6 melanoma cells to lysis by NK cells or TNF, BL6-8 melanoma cells were transfected with cDNA encoding alpha 1,3-galactosyltransferase (alpha 1,3GT). Although the alpha 1,3GT gene-transfected cells expressed alpha-galactosyl epitopes reacting with GS1B4 lectin and reduced sialylation of cell membrane with unmasking SBA lectin-binding carbohydrates, they did not show an increase in tumor cell sensitivity to lysis by NK cells or TNF, indicating that H-2K gene-induced alterations in cell surface carbohydrate expression are not accountable for the observed increase in NK/TNF sensitivity of BL6 melanoma cells. It is possible that the H-2K gene-induced elimination of the endogenous retroviruses might be responsible for the observed increased sensitivity of BL6 melanoma cells to NK cell- and TNF-mediated cytotoxicity.
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PMID:Divergent effects of H-2K and H-2D genes on sensitivity of BL6 melanoma cells to NK cells or TNF-mediated cytotoxicity. 818 Oct 71

We have developed a sensitive and quantitative RT-PCR assay for the determination of tissue factor (TF) mRNA levels in human cells. An in vitro synthesized internal standard RNA was used to correct for differences in reverse transcription or amplification of various RNA samples. The PCR products were quantitated by hybridization. The sensitivity was such that less than 0.2 microgram of total endothelial RNA sufficed to measure its TF mRNA content. The RT-PCR assay was used to determine TF mRNA levels in endothelial cells treated with a factor from human melanoma cells and/or TNF. In this way the amount of TF mRNA could be induced to a level that was at least 80-fold higher than that in non-induced cells. This increase was in the same order of magnitude as the induction of measured TF activity.
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PMID:Measurement of tissue factor messenger RNA levels in human endothelial cells by a quantitative RT-PCR assay. 819

Twenty-seven patients treated with high-dose rTNF alpha, IFN gamma and melphalan by isolated limb perfusion were histologically documented. There were 20 cases of melanoma-in-transit metastases and 7 cases of high-grade soft-tissue sarcoma. Biopsies were taken before IFN gamma, after IFN gamma, before TNF alpha and between 2 hr and 60 days after the TNF alpha perfusion. Immunohistochemistry was performed for adhesion molecules ICAM-I, ELAM-I (E selectin), VCAM-I and PECAM. During the first hours after beginning perfusion, the endothelial cells of the tumour capillaries appeared swollen. Significant tumour necrosis was already observed 3 hours after the perfusion in melanoma cases. The overall predominant feature was coagulative necrosis associated or not with haemorrhagic necrosis. TNF alpha induced increased expression of ELAM-I and VCAM-I adhesion molecules on intratumoral endothelial cells. The activated tumour vessels were progressively destroyed. Significant intravascular recruitment of polymorphonuclear cells (PMNs) was observed 3 hr after starting TNF alpha; it was followed by diapedesis and tumour colonization 3 days later. T lymphocytes and macrophages were detected during the first 7 days and B lymphocytes during the second week. Melanoma in transit metastases treated with alkylating agent alone did not show significant necrosis and did not express high levels of adhesion molecules (ELAM-I, VCAM-I) nor infiltration by PMN.
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PMID:Early endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha (rTNF alpha). 819 73

Treatment of B16 melanoma-bearing mice with recombinant tumour necrosis factor (rTNF) caused a marked inhibition of tumour growth but did not result in the complete cure of the tumour-bearing mice. In contrast, combination therapy of B16-bearing mice with r-TNF and recombinant interleukin 2 (rIL-2) potentiated the therapeutic effect of rTNF and 30% of the mice were totally cured from tumour. Spleen cells obtained from B16-bearing mice showed markedly decreased immune responses including IL-2 production, IL-2 responsiveness and mixed lymphocyte reaction owing to the existence of suppressor macrophages. However, spleen cells obtained from mice cured with rTNF plus rIL-2 showed the same level of T cell responsiveness as that from normal mice. The decreased induction of alloantigen-specific cytotoxic T lymphocytes (CTL) in B16-bearing mice was also recovered after treatment with rTNF plus rIL-2. Moreover, B16-specific CTL, which could not be induced in normal or B16-bearing mice, was effectively induced from the spleen cells of B16-cured mice by rTNF and rIL-2. These results demonstrated that local therapy of melanoma with rTNF and rIL-2 was effective and induced systemic antitumour immunity in vivo.
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PMID:Potentiation of therapeutic effect of recombinant tumor necrosis factor against B16 mouse melanoma by combination with recombinant interleukin 2. 821 34

Interleukin (IL)-7 has been evaluated for its influence, alone or in combination with local hyperthermia (LH), on B16a melanoma-bearing mice. Six- to eight-week-old C57BL/6J male mice were inoculated s.c. with 5 x 10(5) tumor cells into the left hind limb. Mice were randomly divided into four groups, and treated s.c. with IL-7 (5 ng) or saline as control, twice a day for three weeks beginning eight days after tumor inoculation. LH, using hot water circulator at 43 +/- 0.2 degrees C for 30 min, was induced to the limb with tumor twice a week for two weeks. Size of the primary tumor was measured every other day for five weeks. Mice were sacrificed five weeks after tumor inoculation. The size of the primary tumor and the number of lung metastases were reduced in mice treated either with IL-7 or LH alone. As a control for IL-7, granulocyte colony stimulating factor (G-CSF) alone had no effect on primary tumor size or number of lung metastases. The greatest antitumor effect was observed in mice treated with IL-7 in combination with LH. Survival was prolonged significantly only in mice treated with IL-7 plus LH compared with that of mice treated with saline. Decreased natural killer (NK) cell activity, number of Thy1.2 cells, and ratio of L3T4+/Lyt2+ cells were associated with tumor growth. These parameters were restored in mice treated with IL-7 plus LH. Increases in levels of IL-1 alpha, IL-6, tumor necrosis factor (TNF alpha) and interferon (IFN gamma) were associated with an increase in the survival of tumor-bearing mice treated with IL-7 and/or LH. These results suggest that changes in T-cell, NK cell and cytokines such as IL-1 alpha, IL-6, TNF-alpha and IFN-gamma in response to IL7 and/or LH might account for prolonged survival of B16a melanoma-bearing mice and that IL-7 might be useful as a potential antitumor agent combined with other therapy in certain malignant solid tumors with metastases.
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PMID:Antitumor effect of interleukin 7 in combination with local hyperthermia in mice bearing B16a melanoma cells. 824 52

We have characterized constitutive and cytokine-regulated MGSA/GRO alpha, -beta, and -gamma gene expression in normal retinal pigment epithelial (RPE) cells and a malignant melanoma cell line (Hs294T) to discern the mechanism for MGSA/GRO constitutive expression in melanoma. In RPE cells, constitutive MGSA/GRO alpha, -beta, and -gamma mRNAs are not detected by Northern (RNA) blot analysis although nuclear runoff experiments show that all three genes are transcribed. In Hs294T cells, constitutive MGSA/GRO alpha expression is detectable by Northern blot analysis, and the level of basal MGSA/GRO alpha transcription is 8- to 30-fold higher than in RPE cells. In contrast, in Hs294T cells, basal MGSA/GRO beta and -gamma transcription is only twofold higher than in RPE cells and no beta or gamma mRNA is detected by Northern blot. These data suggest that the constitutive MGSA/GRO alpha mRNA in Hs294T cells is due to increased basal MGSA/GRO alpha gene transcription. The cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) significantly increase the mRNA levels for all three MGSA/GRO isoforms in Hs294T and RPE cells, and both transcriptional and posttranscriptional mechanisms are operational. Nuclear runoff assays indicate that in RPE cells, a 1-h IL-1 treatment induces a 10- to 20-fold increase in transcription of MGSA/GRO alpha, -beta and -gamma but only a 2-fold increase in Hs294T cells. Similarly, chloramphenicol acetyltransferase (CAT) reporter gene analysis using the MGSA/GRO alpha, -beta, and -gamma promoter regions demonstrates that IL-1 treatment induces an 8- to 14-fold increase in CAT activity in RPE cells but only a 2-fold increase in Hs294T cells. The effect of deletion or mutation of the MGSA/GRO alpha NF-kappa B element, combined with data from gel mobility shift analyses, indicates that the NF-kappa B p50/p65 heterodimer in RPE cells plays an important role in IL-1- and TNF alpha-enhanced gene transcription. In Hs294T cells, gel shift analyses indicate that IL-1 and TNF alpha induce NF-kappa B complex formation; however, transactivation does not occur, suggesting that subtle differences in the NF-kappa B complexes may result in the inability of the cytokines IL-1 and TNF alpha to activate transcription of the MGSA/GRO genes. IL-1 and TNF alpha posttranscriptionally regulate MGSA/GRO mRNA levels in both cell types. In Hs294T cells, IL-1 increases the half-life of MGSA/GRO alpha from 15 min to 6 h (a 24-fold increase in half-life). These data indicate that IL-1 and TNF alpha transcriptionally and posttranscriptionally regulate MGSA/GRO alpha, -beta, and -gamma mRNA levels in RPE cells, while in Hs294T cells, the major effect of IL-1 and TNF alpha is on mRNA stability.
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PMID:MGSA/GRO transcription is differentially regulated in normal retinal pigment epithelial and melanoma cells. 826 46

A human melanoma cell line (A375-6) became resistant to the anti-proliferative effect of human IL-1 after a long period of culture. Two stable resistant sub-clones were obtained, and the mechanism of the IL-1 resistance was investigated. Resistant cells, but not sensitive cells, appeared to produce constitutively IL-1 activity. The activity was neutralized by anti-IL-1 alpha antibody but not by anti-IL-1 beta antibody. Resistant cells expressed IL-1 alpha but not IL-1 beta mRNA. Therefore, the resistant cells appeared to produce IL-1 alpha mRNA for IL-1 receptor antagonist (IL-1Ra) was not detected in resistant cells, indicating that the resistance is not attributable to IL-1Ra. These resistant cells were also resistant to the anti-proliferative effect of human IL-6, but not to that of human TNF. Resistant cells appeared to produce constitutively IL-6 more than sensitive cells, and IL-6 production both in sensitive and in resistant cells was augmented by exogenous IL-1. Furthermore, constitutive production of IL-6 in resistant cells was inhibited by IL-1Ra. Type I IL-1 receptor (IL-1R) mRNA was expressed equally in resistant and sensitive cells. These data indicate that the resistance is not the result of loss of functional IL-1R and that IL-1 induces IL-6 in an autocrine manner. It is, therefore, conceivable that endogenous IL-1 and IL-6 contribute to IL-1 resistance.
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PMID:Resistance to the anti-proliferative effect of IL-1 on human melanoma cell line is associated with endogenous production of IL-1 and IL-6. 831 11


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