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)

Two membrane subfractions, one enriched in GM3 ganglioside and the other containing caveolin, were separated from low density detergent-insoluble membrane fraction prepared by sucrose density gradient centrifugation of postnuclear fraction of mouse melanoma B16 cells. The GM3-enriched subfraction, separated by anti-GM3 monoclonal antibody DH2, contained sphingomyelin, cholesterol, c-Src, and Rho A but not caveolin. In contrast, the caveolin-containing subfraction, separated by anti-caveolin antibody, contained neither GM3, c-Src, nor Rho A but did contain glucosylceramide, Ras, a very small quantity of sphingomyelin, and a very large quantity of cholesterol. The GM3/c-Src-enriched membrane subfraction was characterized by (i) maintenance of GM3-dependent adhesion and (ii) susceptibility to being activated for signal transduction through GM3. 32P-Phosphorylation of c-Src (Mr 60,000) together with two other components (Mr 45,000 and 29,000) was enhanced in the fraction bound to dishes coated with asialo-GM2 (Gg3) or with anti-GM3 monoclonal antibody DH2, detected by incubation with [gamma-32P]ATP at 37 degreesC for 5 min. GM3-dependent adhesion of B16 cells to Gg3-coated dishes and associated signaling were not reduced or abolished in the presence of either filipin or nystatin, which are cholesterol-binding reagents known to abolish caveolae structure and function. B16 melanoma cells incubated with filipin (0.16-0.3 micrograms/ml) or with nystatin (25 micrograms/ml) for 30 min showed depletion of cholesterol in detergent-insoluble membrane fraction but were still capable of binding to Gg3-coated plate and capable of the associated signaling. Thus, the GM3-enriched subfraction, involved in cell adhesion and capable of sending signals through GM3, represents a membrane domain distinguishable from caveolin-containing subfraction or caveolae. This microdomain is hereby termed the "glycosphingolipid signaling domain" or "glycosignaling domain".
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PMID:Separation of "glycosphingolipid signaling domain" from caveolin-containing membrane fraction in mouse melanoma B16 cells and its role in cell adhesion coupled with signaling. 983 65

Until recently, the prognosis of patients with deep primary melanomas or regionally metastatic nodal disease has been poor, with 5-year survival rates of 25-50%. The results of the Eastern Cooperative Oncology Group (ECOG) trial 1684 represent the first evidence of effective adjuvant therapy for these patients. Interferon alfa-2b (IFN-alpha 2b) administered at maximally tolerated doses for 1 year significantly improved both relapse-free and overall survival. The impact of interferon therapy was observed early during treatment and the effect was durable. The results of this trial represent a breakthrough in the treatment of high-risk resected cutaneous melanoma and identify the new reference standard for new cytokines, vaccines and combinations. The favourable results provide a strong impetus for redoubled research into immunotherapy for treatment of melanoma. Specifically, ganglioside vaccines have been identified that induce antibody responses and may affect patient outcome and peptide/protein vaccines that are recognised by the T-cell have been identified in large numbers. ECOG and the U.S. Intergroup are conducting a phase III trial (E1694) that compares GM2 vaccine to IFN-alpha 2b and a phase II trial evaluating concurrent or sequential use of interferon and vaccines for patients with resectable melanoma. They are also planning phase II trials of peptides for patients with metastatic unresectable melanoma. Laboratory analyses of the immune responses induced by IFN and the several vaccines are anticipated to reveal the fundamental immune mechanisms that are important for relapse-free survival and immunological control of melanoma.
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PMID:Systemic adjuvant treatment of high-risk melanoma: the role of interferon alfa-2b and other immunotherapies. 984 3

Trials in high-risk melanoma patients evaluating the role of postoperative adjuvant treatment with interferons or other cytokines, ganglioside-based vaccines, or vaccines based on melanoma cells are ongoing or planned internationally. In Europe, the two largest randomised trials are carried out by the European Organization for Research and Treatment of Cancer-Melanoma Cooperative Group (EORTC-MCG). In stage IIA patients (T3N0M0) with a moderate risk of micrometastatic disease (35-40%), Trial 18,961 compares observation with ganglioside GM2 vaccination. This trial will be activated during the spring of 1998 and is expected to enrol 1000 patients. In stage IIB-IIIB (T4N0M0-TxN12M0) patients with a high risk of micrometastatic disease (approximately 80%), trial 18,952 compares observation with adjuvant therapy using two intermediate dosage regimens of interferon alfa-2b (IFN-alpha 2b). These trials and the philosophy of the EORTC-MCG programme allow more toxic treatment regimens to be investigated in patients with high-risk disease and only treatments with minimal toxicity to be evaluated in patients with moderate- to low-risk disease. Recently completed and other ongoing trials also are discussed. Overall, if clinical efficacy is demonstrated, the toxicity, impact on quality of life and treatment costs determine the acceptance and applicability of a treatment.
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PMID:Strategy of the EORTC-MCG trial programme for adjuvant treatment of moderate-risk and high-risk melanoma. 984 5

Polyclonal immunoglobulin M antibodies to the monosialoganglioside GM2, sulfoglucuronyl glycolipids, and sulfatide were detected by thin-layer chromatography and enzyme-linked immunosorbent assay in the serum of a patient with melanoma and chronic inflammatory demyelinating polyneuropathy. Both the patient's serum and polyclonal antibodies against GM2 reacted strongly with a biopsy of melanomatous tissue from the patient, suggesting a process of molecular mimicry.
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PMID:Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma. 985 37

Gangliosides are neuraminic acid-containing glycosphingolipids that are anchored into the cell membrane lipid bilayer by lipophilic ceramide chains. They are overexpressed on tissues of neuroectodermal origin, and particularly in tumors such as melanomas, sarcomas, neuroblastomas, astrocytomas, and small cell lung cancers. Both active and passive immunotherapy trials have identified gangliosides as uniquely effective targets for antibody mediated melanoma immunotherapy. Induction of antibodies against GM2 by vaccination has correlated with an improved prognosis in American Joint Committee on Cancer (AJCC) stage III melanoma patients and vaccines containing GM2 chemically conjugated to keyhole limpet hemocyanin (KLH; GM2-KLH) plus the immunologic adjuvant QS-21 have proven to be consistently immunogenic. Phase III trials with this vaccine are ongoing in patients with melanoma in the United States, Canada, Europe, Australia, and New Zealand. GD2, fucosylated GMI, and GD3-KLH conjugates plus QS-21 are also consistently immunogenic, inducing IgM and IgG antibodies in the majority of patients. Polyvalent ganglioside-KLH conjugate plus QS-21 vaccines should be available in early 1999 for testing in phase II and III clinical trials.
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PMID:Ganglioside vaccines with emphasis on GM2. 986 78

The patterns of ganglioside profiles were studied in 10 human glioma and one melanoma cell lines. Ganglio-series gangliosides, GM3 (NeuAc alpha2-3Gal beta1-4Glc beta1-Cer) and GM2 (GalNAc beta 1-4 (NeuAc alpha2-3)Gal beta1-4Glc beta 1-1Cer), and a neolacto-series ganglioside, sialylparagloboside (SPG) (NeuAc alpha 2-3Gal beta1-4GlcNAc beta1-3Gal beta1-4Glc beta1-1Cer), were the predominant constituents. The activities of the two key enzymes, GM3 synthetase and lactotriaosyl ceramide (Lc3Cer) synthetase, alone did not account for the ganglioside profile. Metabolic labeling with the use of [3H]glucosamine-HCl showed more pronounced difference in the synthetic rate of each ganglioside type, in which GM2 was the most strongly labeled in 7 out of the 10 glioma cell lines. On quantifying the chemical content of GM3 and GM2, the GM3/GM2 molar ratio of above 2.0 was arbitrarily classified into GM3 dominant type (KG-1C and Mewo); the ratio below 0.5 was designated as GM2 dominant type (H4, U138MG, U373MG, T98G and A172); and the ratio between 0.5 and 2.0 was regarded as GM3 and GM2-co-dominant type (U87MG, Hs683, SW1088 and U118MG). Subsequently, the capabilities of the antibody binding to these gangliosides were examined in native forms in the cell membrane and in chemically-isolated forms. The intensity of reaction against chemically isolated GM3 and GM2 gangliosides was dependent on the quantity, and GM2 was more reactive than GM3; however, the reactivities on the cell surface did not correlate with the chemical content indicating other factors to influence their immunoreactivities.
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PMID:Chemical, metabolic and immunological characterization of gangliosides of human glioma cells. 992 80

Most human neuroblastoma tumors are characterized by the high expression of GD2 (or GD2 and/or GM2) gangliosides, whereas melanomas characteristically express GD3 ganglioside. The molecular basis for these patterns was investigated by examining the relationship between ganglioside levels, glycosyltransferase (GM2/GD2 synthase and GD3 synthase) activity, and corresponding mRNA levels in a panel of human neuroblastoma and melanoma cell lines. In general, the ganglioside patterns could be explained by the levels of the transferases and their mRNA, indicating control at the level of transcription. A key role was noted for GD3 synthase. Notably, it was found that neuroblastoma cell lines with high GD2 ganglioside levels had low levels of GD3, its synthase, and mRNA for the enzyme even though this step provides the substrate for GD2 synthesis. The key role for GD3 synthase was also examined by stably transfecting GD3 synthase cDNA into a neuroblastoma cell line (SH-SY5Y) not expressing GD3 and GD2. The resulting cell line had high levels of GD2 ganglioside and altered morphology and growth characteristics.
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PMID:Relationship of glycosyltransferases and mRNA levels to ganglioside expression in neuroblastoma and melanoma cells. 993 Jul 22

Melanoma cells express ganglioside antigens GM3, GD3, GM2, and GD2 on their surface. This study examined whether immunization with a melanoma cell vaccine induced anti-ganglioside antibody responses in melanoma patients and whether these responses were correlated with survival. Sixty-six patients who had received melanoma cell vaccine immunotherapy after surgical removal of regional metastatic melanoma were identified. Cryopreserved serum samples from these patients were used in an enzyme-linked immunsorbent assay to determine the IgM antibody levels to GM2, GD2, GM3, and GD3 prior to melanoma cell vaccine treatment and 4 wk after the first melanoma cell vaccine immunization. All antibody levels significantly increased by week 4 (p < 0.001 for all four antibodies) and all increases were significantly associated with survival (anti-GD2, p < 0.001; anti-GM2, p = 0.001; anti-GD3, p < 0.001; anti-GM3, p < 0.001). Anti-tumor activity of these antibodies was proved using five representative antibody-positive sera in a complement-dependent cytotoxicity assay with cultured melanoma cell lines. These studies suggest that GM2, GD2, GM2, and GD3 expressed by melanoma cells can induce specific IgM antibodies and that high levels of these antibodies might have a beneficial impact on survival.
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PMID:IgM anti-ganglioside antibodies induced by melanoma cell vaccine correlate with survival of melanoma patients. 998 97

Although small cell lung cancer (SCLC) is highly responsive to chemotherapy, relapses are common, and most patients die within 2 years of diagnosis. After initial therapy, standard treatment is observation alone. We have been investigating immunization against selected gangliosides as adjuvant therapy directed against residual and presumably resistant disease persisting after chemotherapy and irradiation. Previously, we reported that the presence of anti-GM2 ganglioside antibodies is associated with a prolonged disease-free survival in patients with melanoma, and that SCLC patients immunized with BEC2, an anti-idiotypic monoclonal antibody that mimics the ganglioside GD3, had a prolonged survival compared with historical controls. In the present trial, fucosyl-alpha1-2Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3) Galbeta1-4Glcbeta1-1Cer (Fuc-GM1), a ganglioside expressed on the SCLC cell surface, was selected as a target for active immunotherapy. Fuc-GM1 is present on most SCLCs but on few normal tissues. SCLC patients achieving a major response to initial therapy were vaccinated s.c. on weeks 1, 2, 3, 4, 8, and 16 with Fuc-GM1 (30 microg) conjugated to the carrier protein keyhole limpet hemocyanin and mixed with the adjuvant QS-21. Ten patients received at least five vaccinations and are evaluable for response. All patients demonstrated a serological response, with induction of both IgM and IgG antibodies against Fuc-GM1, despite prior treatment with chemotherapy with or without radiation. Posttreatment flow cytometry demonstrated binding of antibodies from patients' sera to tumor cells expressing Fuc-GM1. In the majority of cases, sera were also capable of complement-mediated cytotoxicity. Mild transient erythema and induration at injection sites were the only consistent toxicities. The Fuc-GM1-KLH + QS-21 vaccine is safe and immunogenic in patients with SCLC. Continued study of this and other ganglioside vaccines is ongoing.
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PMID:Immunogenicity of a fucosyl-GM1-keyhole limpet hemocyanin conjugate vaccine in patients with small cell lung cancer. 1053 41

The gangliosides GD3, GD2 and GM2 are expressed on the cell surface of malignant melanomas, GD3 being the most abundant. We have shown that immunization of melanoma patients with GM2 adherent to Bacillus Calmette-Guerin (GM2/BCG) induced an IgM antibody response. Vaccines containing GM2-keyhole limpet hemocyanin (KLH) conjugate and the immunological adjuvant QS-21 induced a higher titer IgM response and consistent IgG antibodies. Patients with antibodies against GM2 survived longer than patients without antibody. On the other hand, our previous trials with GD3/BCG, GD3 derivatives including GD3-lactone (GD3-L)/BCG failed to induce antibodies against GD3. In our continuing efforts to induce antibody against GD3, we have immunized groups of 6 melanoma patients with GD3-KLH or GD3-L-KLH conjugates containing 30 microg of ganglioside plus 100 microg of QS-21 at 0, 1, 2, 3, 7 and 19 weeks. Prior to vaccination, no serological reactivity against GD3 or GD3-L was detected. After immunization, IgM and IgG antibodies were detected against both GD3 and GD3-L in the GD3-L group exclusively. The GD3-L-KLH vaccine induced IgM titers against GD3-L of 1:40-1/1,280 in all patients and IgG titers of 1/160-1/1,280 in 4 patients. These antibodies also strongly cross-reacted with GD3. ELISA reactivity was confirmed by immune thin-layer chromatography on GD3 and melanoma extracts. Sera obtained from 4 of these 6 patients showed cell surface reactivity by FACS and from 2 showed strong cell surface reactivity by immune adherence (IA) assay and complement lysis against the GD3 positive cell line SK-Mel-28.
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PMID:Induction of antibodies against GD3 ganglioside in melanoma patients by vaccination with GD3-lactone-KLH conjugate plus immunological adjuvant QS-21. 1069 46


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