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 immunogenicity of the disialoganglioside, GD3, a melanoma-tumor-associated antigen, has been evaluated in non-human primates. Sera from four chimpanzees and two monkeys were evaluated for anti-GD3 antibody activity by solid-phase radioimmunoassay using GD3 and control gangliosides as targets. Serum from one monkey, immunized with cells from a melanoma cell line, was strongly reactive with GD3, having a titer of greater than 2500. In contrast, serum from this animal was non-reactive with several other gangliosides including the structurally similar GM3. Anti-GD3 reactivity was also demonstrable, albeit in low titer, in the sera of an additional monkey and a chimpanzee. Each of these animals had likewise been immunized using cells from melanoma cell lines. On the basis of these observations, suggestive of a primate anti-GD3 antibody response, we initiated a series of immunizations of chimpanzee using purified GD3 bound to Salmonella minnesota, R595. IgG reactive with melanoma cells in the cell-binding assay was first detected in sera collected after 4 immunizations and increased in titer against each reactive melanoma cell line during the immunizations. Reactivity of this serum with melanoma cell lines demonstrated a direct correlation with the expression of GD3 by the respective cell line. Anti-GD3 reactivity was evident in solid-phase radioimmunoassay against purified GD3 beginning with serum collected after 11 immunizations. By comparison with its binding to the control ganglioside panel, this serum demonstrated strong specificity for GD3 (titer = 640) while having only marginal reactivity with GM3 (titer = 40). Immune serum from this animal was also able specifically to block subsequent binding of a murine IgM anti-GD3 antibody (DMab7) to target GD3 in solid-phase radioimmunoassay. Together, these observations suggest that GD3, in the form of a purified molecule bound to a bacterial matrix or as part of the intact melanoma cell membrane, can be immunogenic in non-human primates, and is able to elicit an antibody response of appropriate specificity.
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PMID:Serological response of non-human primates to human melanoma disialoganglioside GD3. 273 Nov 85

Gangliosides appear to be important target molecules for immunological effector mechanisms on neuro-ectodermal tumors. Therefore in vitro studies were performed to examine whether ganglioside GD3, which is highly expressed on the cell surface of cultured human melanoma cells, is being shed into the culture medium. Measurable quantities of gangliosides GM3 and in particular GD3 were shed by the melanoma cells we have tested as detected on thin-layer chromatograms (TLC) stained with orcinol. Ganglioside GD3 was also evidenced by immunostaining with anti-GD3 MAb and by ELISA. The concentration of GD3 in the supernatant of human melanoma cells depended on the ganglioside pattern of the cell line. Cells containing high levels of GD3 shed large amounts, cells with low levels shed no detectable GD3. Ganglioside GD3 was detectable in sera, but no major quantitative differences were observed in sera of patients with GD3-positive tumors and normal controls. This points to a local accumulation of ganglioside GD3 at the tumor site.
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PMID:Ganglioside GD3 shedding by human malignant melanoma cells. 274 85

Experience with antibody-dependent, cell-mediated cytotoxicity (ADCC) has shown that antibody can increase the localization and killing capacity of lymphocytes. We tested the possibility of improving the activity of lymphokine-activated killer cells (LAK) on human tumor using the subrenal capsule assay in nude mice. The tumors were first grown in the renal capsule space and the effector cells injected later. In the model experiment we used M21 melanoma and monoclonal antibody against melanoma-associated antigen GD3. This antibody increases the tumor inhibitory activity of LAK cells from healthy donors in comparison to LAK alone. We have been able to prove the clinical relevance of such an approach. Tumor bioptic material from five tumor patients was tested with various monoclonal antibodies, following which the highly reactive antibodies were selected and incubated with the patient's LAK cells. Such pretreated LAK cells have a high growth-inhibitory effect on autologous tumor growing in the renal capsule space of the test mice.
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PMID:Use of the subrenal capsule assay to measure antibody-dependent, cell-mediated cytotoxicity against head and neck tumors. 275 64

Levels of GD2, GD3, and 9-O-acetyl GD3 were monitored in sera of patients with melanoma and healthy adults with two monoclonal antibodies that specifically detect these gangliosides. By direct measurement of radioactivity in the immunolabeled chromatogram, GD2 could be detected in normal sera at 2 ng/mL. Serum levels of GD2 and GD3 were increased approximately sixfold and fivefold, respectively, in patients with disseminated melanoma, compared with those of healthy adults. The acetylated derivative of GD3, which is highly specific for melanoma cells, was not detected in serum. This sensitive assay allows the quantitation of tumor-associated gangliosides that are circulating in sera of melanoma patients.
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PMID:Levels of disialogangliosides in sera of melanoma patients monitored by sensitive thin-layer chromatography and immunostaining. 277 37

In human tumors of neuroectodermal origin cell surface expression of individual gangliosides is either increased or decreased relative to comparable normal cells. We have previously shown that gangliosides shed from melanoma cells can immunomodulate T cell activity. Monocytes/macrophages (m/m) are known to play an important role as accessory and effector cells in immune responses. We therefore investigated the effect of exogenous gangliosides derived from melanoma on m/m functions in vitro. Gangliosides commonly expressed on human melanoma such as GM3, GD3, GM2, and GD2 were investigated, as well as GM1, a major component of human neural tissue. Monocytes were isolated from human peripheral blood mononuclear cell populations, treated with gangliosides in vitro, and evaluated in several functional assays. Treatment of m/m with GM2 and GM3 gave the greatest inhibition of Fc receptor expression. GM1 and GD3 on the other hand most inhibited the production of interleukin-1 (IL-1) by m/m. Production of tumor necrosis factor (TNF) like monocytoxin was not affected by incubation with individual gangliosides. These studies suggest that individual melanoma gangliosides have different regulatory effects on m/m functions.
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PMID:Modulation of human macrophage functions by gangliosides. 278

Human melanoma cells express high levels of GM3 and GD3 gangliosides whereas normal melanocytes have only low levels of GD3 but maintain their expression of GM3. In order to understand the basis for this difference, the levels of the sialyltransferase that converts GM3 to GD3 (CMP-N-acetylneuraminic acid:GM3 sialyltransferase or GD3 synthase, EC 2.4.99.8) were analyzed in melanoma and other cell lines. Enzyme levels were determined in vitro using membrane preparations and measuring the addition of [14C]-N-acetylneuraminic acid from CMP-[14C]-N-acetylneuraminic acid to GM3 in the presence of Triton CF-54. Sialyltransferase levels in 44 human cancer cell lines (including melanoma, neuroblastoma, astrocytoma, various carcinomas, and leukemias) and cultures of normal melanocytes and kidney epithelial cells were compared, and the products were identified by thin layer chromatography and fluorography. Melanoma cell lines exhibited the highest levels of incorporation and GD3 was found to be the major product. GM3 was also formed, apparently from endogenous lactosylceramide. Very low levels of GD3 synthase were found in normal melanocytes. Neuroblastoma and some astrocytoma cell lines also had significant levels of GD3 synthase. Some other cell lines incorporated high levels of radioactivity but the products did not correspond to GD3 and the major product was usually GM3. In general the levels of GD3 synthase correlated with the expression of GD3 in the various cell types. These results point to higher levels of GD3 synthase being directly responsible for the enhanced expression of GD3 in melanoma.
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PMID:Sialyltransferase levels and ganglioside expression in melanoma and other cultured human cancer cells. 280 71

Human monoclonal antibodies (mAbs) were prepared from the lymph node and peripheral blood lymphocytes (PBL) of the patients with melanoma. NS-1 fusion with lymph node lymphocytes resulted in a higher number of growing hybrids than LICR-LON-HMy2 (LICR-2) fusion. Virtually no hybrids were obtained from NS-1 or LICR-2 fusions with PBL. Epstein-Barr virus transformed the lymphocytes from lymph node and periphered blood with equal efficiency, and the yield of proliferating cultures for antibody screening was more than 10 to 30-fold greater than that obtained by fusion techniques. However, once antibody-producing cultures had been identified, stability and clonability of EBV-transformed cells were poorer than that of NS-1 hybrid cells. To combine the strengths of both methods, cultures of EBV-transformed cells were fused with NS-1, and hybrid clones were isolated that showed vigorous growth, clonability, and stable antibody secretion. Detailed specificity analysis of four mAbs indicated detection of a class 1 (unique) melanoma antigen (GXM1), a class 2 (shared) melanoma antigen (HJM1) and two class 3 (widely distributed) antigen (FCM1 and DSM1). HJM1 reacted most strongly with GD3 and would be a candidate for immunotherapy of melanoma.
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PMID:[Preparation of human monoclonal antibodies reactive with human melanoma and the possibility of clinical application]. 283 35

Based on the clinicopathological delineation of distinct steps of tumor progression in the melanocytic system, the in vitro behavior of melanocytes with increasing malignant potential has been investigated. Tumor progression in melanocytes is characterized by an increasing growth autonomy and decreased requirement but enhanced utilization of exogenously provided polypetide growth factors (EGF, IGF-I). The endogenous production of growth factors such as alpha-TGF, PDGF, and bFGF by metastatic melanoma cells might contribute to their independence from exogenously provided factors. Although expression of some melanoma-associated antigens in vivo is detectable only on malignant cells, propagation of normal melanocytes in tissue culture leads to expression of the majority of these antigens. Many of these antigens can be grouped into functionally defined categories, including growth factor receptors, extracellular matrix proteins, and cell-substrate interacting antigens. One cell-substrate interacting antigen, the GD2/GD3 ganglioside, appears to play a critical role in the metastatic process of melanoma cells. The successful propagation and characterization of melanocytic cells of all stages of tumor progression in tissue culture provide a unique human experimental model for the study of mechanisms of malignant transformation.
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PMID:Characteristics of cultured human melanocytes from different stages of tumor progression. 290 75

The fine specificity analysis of two human monoclonal antibodies (AbFCM1 and AbHJM1) reacting with gangliosides is described and their specificities are compared with analogous mouse monoclonal antibodies (mAbs). These two antibodies were generated from lymphocytes of melanoma patients by Epstein-Barr virus transformation followed by fusion with mouse myeloma NS-1. Using a wide variety of gangliosides, including N-glycolylneuraminic acid (NeuGc)-containing compounds, the precise structures recognized by these two antibodies were elucidated by enzyme-linked immunosorbent assay and immunostaining of thin-layer chromatograms. AbFCM1 reacted with N-acetylneuraminic acid (NeuAc)-type GM3, GD1a, sialylparagloboside, and GT1b in decreasing order of intensity. This antibody also reacted with (NeuAc-NeuGc-)-GD3 and -disialylparagloboside, but did not react with NeuGc-type GM3, GM2, sialylparagloboside, (NeuGc)2-GD3 and -disialylparagloboside. The main epitope structures recognized by AbFCM1 are, therefore, NeuAc alpha 2----3Gal beta 1- and NeuAc alpha 2----8NeuGc alpha 2----Gal beta 1-. These results are similar to the specificity of mouse mAb M2590. AbHJM1 reacted with NeuAc-type GD3 and disialylparagloboside, GD2, GD1b, GM3, and GT1b, in decreasing order of intensity. Among NeuGc-type gangliosides, this antibody reacts with (NeuAc-NeuGc-)-GD3 and -disialylparagloboside, but did not react with gangliosides containing only NeuGc. Consequently the epitope structure recognized by AbHJM1 is probably (R)-(NeuAc alpha 2----8Sialic acid alpha 2----3)Gal beta 1-. Mouse anti-GD3 mAbR24, in contrast, showed strong reactivity only with GD3 and -disialylparagloboside among NeuAc-type gangliosides, but showed a similar pattern to AbHJM1 in its reactivity with NeuGc-containing gangliosides. Although these two human monoclonal antibodies are not highly restricted in their specificities, they reacted best with the major gangliosides, GM3 and GD3, present in the majority of human melanomas.
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PMID:Two human monoclonal antibodies reacting with the major gangliosides of human melanomas and comparison with corresponding mouse monoclonal antibodies. 290 45

The rapidly expanding list of monoclonal antibodies (MAbs) to human cell surface antigens provides reagents to probe the biology of malignant melanoma and to develop new diagnostic and therapeutic approaches to this disease. The criteria used to select MAb-defined antigens as targets for passive immunotherapy or immunolocalization of melanoma include: 1) consistent antigen expression in melanomas, 2) restricted antigen distribution in normal tissues and nonmelanocytic tumors, and 3) cytotoxic activity of the MAb or MAb conjugates. The present study examined the tissue distribution of three prototype melanoma cell surface antigens, the Mr 57,000 glycoprotein (gp57) recognized by MAb A42, the GD3 ganglioside, and the mel-CSPG chondroitin sulfate proteoglycan. The avidin-biotin immunoperoxidase method was used to examine a large panel of normal tissues and over 150 malignant tumors. It was found that A42 has a highly restricted distribution in normal tissues and is expressed in subsets of melanomas and nonmelanocytic tumors. It was also found that GD3 and mel-CSPG are more widely distributed in normal tissues and among tumors than was thought previously. These immunohistochemical patterns provide an essential data base to evaluate the ongoing clinical trials employing MAbs to GD3 and mel-CSPG for the therapy and immunolocalization of melanomas, and they identify gp57 as a potential marker for subsets of normal and transformed melanocytic cells.
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PMID:Cell surface molecules of human melanoma. Immunohistochemical analysis of the gp57, GD3, and mel-CSPG antigenic systems. 291 50


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