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

The ganglioside GD3 was distributed widely on melanocytes, naevi, and practically all melanomas. Not all the cells in melanoma appeared to express GD3, so that treatment with MAbs to GD3 could be expected to leave foci of tumor cells resistant to the effects of the MAbs. GM3 had a similar distribution of GD3 on melanoma, but was expressed on a lower percentage of cells in individual tumors. Expression of GM3 appeared to be suppressed on melanoma and naevus cells in the epidermis. Addition of MAbs to GM3 to those against GD3 in the treatment of melanoma may increase the lytic effect against cells coexpressing both gangliosides, but as GM3 did not appear to be expressed on GM3 -ve cells, the percentage of resistant cells may not be decreased. GD2 was expressed on only approximately 25% of primaries and less than 50% of metastases. In individual tumors there was some evidence of reciprocal expression of GD3 and GD2, so the combination of MAbs to GD3 and GD2 may decrease the percentage of melanoma cells that are resistant to either MAb alone. Both GD3 and GD2, but not GM3, was expressed on lymphocytes around melanoma metastases in LNs and around melanomas in skin. GD2 was detected on a large percentage of lymphocytes around metastases in lymph nodes, but not in the skin, suggesting that the gangliosides GD2 and GD3 may be expressed on different subsets of T-lymphocytes. These findings, together with previous studies showing that the MAbs can enhance lymphocyte responses to a variety of stimuli, provide support for the hypothesis that the clinical effects of the MAbs may reflect activation of host responses against the tumor. Further analysis of the role of gangliosides in lymphocyte function is needed.
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PMID:Ganglioside antigens in tissue sections of skin, naevi, and melanoma--implications for treatment of melanoma. 167 56

Murine anti-idiotype monoclonal antibodies were generated against a human IgM monoclonal antibody (L612) that recognizes ganglioside GM3 on human melanoma. Hybridomas secreting antibodies that bound specifically to L612 were selected by enzyme-linked immunosorbent assay using L612 and three negative control human IgMs, including monoclonal anti-GM2 and anti-GD2 antibodies, as well as purified serum IgM, as antigen sources. GM3-binding inhibition and cell-binding inhibition assays were used to identify seven anti-idiotype monoclonal antibodies that recognized determinants located within the antigen-combining sites of L612. To determine whether these anti-idiotype monoclonal antibodies possessed the internal image of the original antigen, we immunized syngeneic BALB/c mice with one of the anti-idiotype monoclonal antibodies, 4C10, coupled with keyhole limpet hemocyanin. Sera from the immunized mice reacted strongly with an antigen-positive M12 melanoma cell line and with purified GM3. Because L612 detects and kills melanoma tumor cells in vitro and in vivo in the presence of complement without affecting normal tissues, anti-idiotype monoclonal antibodies carrying the internal image of GM3 may be an effective tool for active specific immunotherapy in patients with melanoma.
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PMID:Anti-idiotype monoclonal antibody carrying the internal image of ganglioside GM3. 170 Jan 34

Gangliosides shed by tumors enhance tumor formation, possibly by suppressing host antitumor immune function, and gangliosides purified from animal tissues and cultured cells inhibit human cellular immune function in vitro. Determination of immunosuppressive activity of highly purified gangliosides, to uncover structure-activity relationships, is therefore important. Here we have studied a series of gangliosides obtained from human tissue and determined their effects on human natural killer (NK) activity. Total gangliosides from human brain tissue were moderately inhibitory; 100 nmol/ml reduced NK activity of human nonadherent PBMC by 43%. The influence of carbohydrate structure upon inhibitory activity was determined by study of eight highly (HPLC) purified individual gangliosides. Of these, we unexpectedly found that the two minor brain gangliosides with the simplest carbohydrate structures, GM2 and GM3, were very active inhibitors (75 and 47%, respectively, at 50 nmol/ml). In contrast, the structurally more complex major species, GM1, GD1a, GD1b, GT1b, and two other minor gangliosides, GD2 and GD3, were inactive. Reduced effector-target binding in a single-cell binding assay by GM2 but not GM3 suggests different mechanisms of inhibition by these two active gangliosides. Since GM2 and GM3 are present in high concentrations in, and are shed by, several common human tumors (e.g., neuroblastoma, melanoma, and glioma), their ability to inhibit NK cytotoxicity supports the hypothesis of a role of shed tumor gangliosides in the enhancement of tumor formation.
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PMID:Immunosuppression by human gangliosides. II. Carbohydrate structure and inhibition of human NK activity. 172 65

Using a specially designed, motorised t.l.c.-f.a.b.-m.s. probe with continuous desorption and scanning over a moving t.l.c. plate, it was shown that glycolipids with identical carbohydrate sequences were well resolved into molecular species with differences in long-chain base and fatty acid. There was no serious diffusion of the glycolipids into the matrix. The technique is demonstrated for sulphatides (one and two sugar residues) isolated from human kidney, GM3 ganglioside isolated from human malignant melanoma, and chemically modified gangliotetraosylceramide from mouse intestine. T.l.c.-f.a.b.m.s. is convenient for sequencing and composition analysis of receptor-active glycolipids, the biological activity of which can be monitored in parallel by overlay on the t.l.c. plate with proteins, viruses, bacteria, or animal cells.
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PMID:The resolution into molecular species on desorption of glycolipids from thin-layer chromatograms, using combined thin-layer chromatography and fast-atom-bombardment mass spectrometry. 181 25

GM3-expressing cells adhere, spread and migrate on plastic plates coated with Gg3, LacCer and Gb4, but not with other glycosphingolipids (GSLs). Thus, cell adhesion, spreading and migration through GSL-GSL interaction occur in an analogous fashion to the interaction of cells with adhesive matrix proteins [AP, e.g. fibronectin (FN), laminin (LN)] through their integrin receptors. In this study, the adhesion of two GM3-expressing cell lines (B16 melanoma and HEL299 fibroblast) on plastic plates co-coated with GSL plus AP is compared with adhesion on plates coated with GSL (Gg3 or LacCer) alone, or coated with AP alone. Results show that: (i) cell adhesion on GSL-coated plates takes place earlier in the incubation period than that on AP-coated plates; (ii) cell adhesion, as well as spreading, was greatly enhanced (in terms of strength and rapidity) on plates co-coated with GSL plus AP; (iii) repulsion (negative adhesion) of cells was observed on plates co-coated with AP plus N-acetyl-GM3 (NAcGM3) and was presumably based on repulsive NAcGM3-NAcGM3 interaction; (iv) GM3-dependent cell adhesion on GSL-coated plates, as well as synergistic promotion of cell adhesion (based on the GSL-GSL and AP-integrin systems), was suppressed by incubation of cells with anti-GM3 monoclonal antibody DH2 or sialidase. Synergistic adhesion of cells on GSL/AP co-coated plates was less inhibited by incubation with peptide sequences RGDS or YIGSR than was adhesion on plates coated with AP alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic effect of two cell recognition systems: glycosphingolipid-glycosphingolipid interaction and integrin receptor interaction with pericellular matrix protein. 182 42

Autoreactive T-cell clones (Thy 1+, CD4+, CD3+) which suppress generation of cytotoxic T lymphocytes (CTL) were established in long-term in vitro culture by stimulation with GM3-liposomes or soluble melanoma (B16) antigen composed of GM3. The T-cell receptors (TCR) of two representative clones analyzed used the same TCR alpha- and V13+ beta-chains. The clones produce only interferon gamma(IFN-gamma) but not interleukins (IL)2 and 4, despite their CD4+ phenotype, suggesting that they are not a typical TH1 or TH2 type. The clones are effectively stimulated by IFN-gamma treated (I-Ab/GM3+) B16 melanoma or I-Ab-transfected GM3+ L cells, but not by GM3-/I-Ab mutant melanoma, EL 4, or I-Ad/k-transfected L cells. This strongly suggested the involvement of GM3/class II in T-cell recognition. Antigen specificity was required for stimulation of the clones. However, once stimulated, they suppressed CTL generation in an antigen non-specific fashion. As class II+ B16 melanoma cells effectively function as antigen-presenting cells to stimulate the autoreactive suppressor T cell (Ts) clones of this type, this negative circuit between class II+ tumor cells and IFN-gamma-producing Ts would be a possible mechanism whereby tumor cells could escape the immune system.
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PMID:Autoreactive T-cell clones which suppress cytotoxic T cell responses. 183 55

Immune cytokines have been shown to play important roles in regulating immune cell functions. Interleukin-4 (IL4), originally described as a B-cell growth factor, is known to activate and differentiate other immune cells. IL4 has been given as an immunotherapeutic to tumor-bearing hosts. In this report, we set out to determine whether IL4 can directly modulate growth and expression of surface antigens on human melanoma cells. The effect of recombinant IL4 alone and in combination with recombinant gamma-interferon (IFN) or recombinant alpha-tumor necrosis factor (TNF) on melanoma cell lines was examined. IL4 significantly inhibited cell growth of all cell lines examined at 100-500 units/ml; but a dose-dependent differential response to individual cell lines occurred. The effect of IL4 was augmented by combination with IFN or TNF. Melanoma-associated ganglioside antigens (GM3, GD3, GM2, GD2) and human leukocyte antigen class I and DR on the cell surface of melanoma cells were assessed by flow cytometry and/or a radiometric binding assay. IL4, IFN, or TNF alone enhanced human leukocyte antigen class I, DR, and beta 2-microglobulin antigen expression. IL4 alone and in combination with IFN or TNF increased the GM3/GD3 ratio expression. GD2 was enhanced significantly by IL4, IFN, and TNF. Pretreatment of melanoma with IL4 or with other cytokines prior to stimulation with peripheral blood lymphocytes significantly enhanced mixed lymphocyte tumor reaction activity as compared with non-treated melanoma used as stimulators. These studies demonstrate that IL4 alone or in combination with IFN and TNF can modulate melanoma growth activity and surface antigen expression to a more differentiated and immunogenic phenotype.
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PMID:Modulation of human melanoma cells by interleukin-4 and in combination with gamma-interferon or alpha-tumor necrosis factor. 190 Dec 39

Several studies have shown that melanoma-associated gangliosides are immunogenic in melanoma patients and that antibodies against them have a favorable prognostic effect. Our study aims at characterizing the humoral immune response in disease-free, advanced melanoma patients vaccinated with a total ganglioside fraction extracted from pooled metastases of human melanoma, containing as major gangliosides GM3 and GD3, and as minor ones GM2 and GD2. Prior to vaccination, all patients were made disease-free by surgical removal of skin, lymph-node or other distant metastases. Repeated vaccinations were carried out intradermally with gangliosides either in the native form in buffered solution, or in the form of liposomes. Serum samples were collected at regular intervals and assayed by ELISA for the presence of specific IgG and IgM antiganglioside antibodies. Selected samples were tested by immunostaining on thin-layer plates to specify the ganglioside species involved in the reactivity. Out of 32 evaluable patients, 17 presented a significant increase in antibody titer, mostly of the IgG isotype, which was maximal between 2 and 4 months after starting injections of gangliosides, and gradually disappeared within 1 year. No significant difference could be seen between the group of 20 patients treated with native gangliosides and the group of 12 vaccinated with the gangliosides in liposomes. All gangliosides seemed to be immunogenic, but GM2 and GD2 were somewhat more reactive. The disease-free intervals for the patients who showed an antibody response to the treatment were significantly higher (p less than 0001) than those of the non-responding group, as compared by the Kaplan-Meier method.
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PMID:Humoral immune response in disease-free advanced melanoma patients after vaccination with melanoma-associated gangliosides. EORTC Cooperative Melanoma Group. 195 94

The carbohydrate structures of the major glycosphingolipids from the liver of the rainbow trout Oncorhynchus mykiss have been examined. We have isolated and identified four major neutral (glucosylceramide, galactosylceramide, lactosylceramide, and globoside) and five acidic (sulfatide, GM3, GM2, GD1a, and 9-O-Acetyl GD3) glycosphingolipids from trout liver. They have been characterized by 1H nuclear magnetic resonance spectroscopy, methylation analysis, fast atom bombardment mass spectrometry, and specific monoclonal antibodies. Significantly, the relatively scarce ganglioside 9-O-acetyl GD3 was found to comprise approximately 23% of the total ganglioside content of normal rainbow trout liver. 9-O-Acetyl GD3 is, however, abundant in human melanoma and as such, trout liver may be a suitable source of this antigen.
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PMID:Isolation and characterization of the major glycosphingolipids from the liver of the rainbow trout (Oncorhynchus mykiss): identification of an abundant source of 9-O-acetyl GD3. 198 25

This report evaluates the relevance of the ratio of the melanoma-associated ganglioside, GD3, and its precursor, GM3, to prognosis and management of Stage II disease. Tumor biopsy specimens from 42 melanoma patients were examined for the ratio and found that GD3 and GM3 constitute 80% of the total lipid bound sialic acids (LBSA) of melanoma. Although the ratio of GM3:GD3 in melanocytes, the progenitors of melanoma, is 19:1 (based on %LBSA), it ranged from 15:1 to 1:5 in tumor biopsy specimens. Patients are categorized into three groups based on their GM3:GD3 ratio (%LBSA) of tumor tissues as Group I (ratio ranged from 15:1 to 1.5:1) (10 of 42), Group II (1.4:1 to 1:1.4) (13 of 42), and Group III (1:1.5 to 1:5) (19 of 42). When the overall survival of patients from the onset of Stage II disease was evaluated among different groups, patients belonging to Group I survived significantly longer than patients of Group II (P = 0.02) and Group III (P = 0.01). Interestingly, Group III expressed immunogenic gangliosides (GD2, GM2, and O-AcGD3) better than the other groups and may benefit more from therapies targeted against these gangliosides antigens. The results of this study indicate that GM3:GD3 ratio is an unusual but well-defined biochemical criteria that may be useful for prognosis and therapeutic management of the disease. Therefore, we propose a routine analysis of the GM3:GD3 ratio of tumors excised after surgery. Screening the ratio is feasible since melanoma expresses a simple profile of gangliosides unlike other forms of cancer.
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PMID:Ganglioside GM3:GD3 ratio as an index for the management of melanoma. 204 49


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