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 groups of S-[2-(N,N-dialkylamino)ethyl]isothiourea derivates which depigmented melanoma cells either with inhibition of tyrosinase (group 1, R = methyl, isopropyl) or without inhibition of tyrosinase (group 2, R = benzyl, phenyl) were studied. Treatment of human melanoma cells with non-lethal doses of group 1 drugs led to a reduction in the levels of mRNA for the pigmentation genes tyrosinase, tyrosinase-related protein-1 and Pmel 17. The group 1 drug S-[2-N,N-diisopropylamino)ethyl[isothiourea] (DINOR) (R = isopropyl) produced only moderate inhibition of DNA, RNA and protein synthesis in three cell lines during the first 24 hr of treatment, and there was no correlation between the extent of inhibition and long-term toxicity. A group 2 drug (R = benzyl) rapidly inhibited DNA synthesis in an amelanotic melanoma cell line (MM96E) sensitive to killing by the drug; association of the latter with inhibition of RNA or protein synthesis was less clear. MM96E cells were also sensitive to killing by reactive oxygen species. In pigmented melanoma cells (MM418), incorporation of [125I]thiouracil, a false precursor of melanin, increased during the first 24 hr of treatment with DINOR whereas a group 2 drug (R = phenyl) inhibited incorporation of [125I]thiouracil. Cells depigmented by treatment with drugs from either group suffered the same amount of DNA damage as pigmented cells after UVB irradiation, as judged by inhibition of DNA synthesis, but did not recover as well as pigmented cells, whether or not drug was present during recovery. The results suggested that (1) group 1 agents down-regulated message for several pigmentation genes, possibly at the transcriptional level; (2) the toxicity of group 2 drugs was related to reactive oxygen species; and (3) melanin protected cells from UVB by enhancing cellular recovery.
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PMID:Reduction of DNA synthesis, pigment synthesis, pigmentation gene mRNA and resistance to UVB in human melanoma cells treated with analogues of a histamine (H2) agonist. 804 13

Cell lineage-specific cellular proteins, oncogenes from viral or cellular origin and tumor suppressor genes encode tumor-specific/associated antigens. Such antigens can elicit an major compatibility complex (MHC) class I-restricted cytotoxic T lymphocyte (CTL) response, either naturally in cancer patients or following appropriate immunostimulation (in vitro or in vivo). The reported immune responses in humans to the melanoma-associated MAGE gene products, GP100 and tyrosinase, all self-proteins, support the idea to use wild-type p53 products as targets for T cells. An important step towards this goal is identification of potential p53 CTL epitopes. We identified the wild-type p53 peptides with the highest affinity to the HLA-A*0201 molecule using two assays: the previously described MHC peptide-binding assay and the peptide competition assay. We obtained CTL against four p53 peptides with a high affinity for the HLA-A*0201 molecule. These findings are discussed next to a short review concerning the p53 literature.
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PMID:p53, a potential target for tumor-directed T cells. 808 74

We recently isolated a cDNA clone that encodes the melanocyte lineage-specific antigen glycoprotein (gp)100. Antibodies directed against gp100 are an important tool in the diagnosis of human melanoma. Since the gp100 antigen is highly expressed in melanocytic cells, we investigated whether this antigen might serve as a target for antimelanoma cytotoxic T lymphocytes (CTL). Here, we demonstrate that cytotoxic tumor-infiltrating lymphocytes (TIL) derived from a melanoma patient (TIL 1200) are directed against gp100. HLA-A2.1+ melanoma cells are lysed by TIL from this patient. In addition, murine double transfectants, expressing both HLA-A2.1 and gp100, are lysed by TIL 1200, whereas transfectants expressing only HLA-A2.1 are not susceptible to lysis. Furthermore, the HLA-A2.1+ melanoma cell line BLM, which lacks gp100 expression and is resistant to lysis, becomes susceptible after transfection of gp100 cDNA. Finally, HLA-A2.1+ normal melanocytes are lysed by TIL 1200. These data demonstrate that the melanocyte differentiation antigen gp100 can be recognized in the context of HLA-A2.1 by CTL from a melanoma patient. Gp100 may therefore constitute a useful target for specific immunotherapy against melanoma, provided that no unacceptable cytotoxicity towards normal tissue is observed.
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PMID:Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. 811 68

Human melanoma cells, but not tumor cells of other histological origin, express a unique membrane-associated glycoprotein, designated ME20-M, and secrete a soluble glycoprotein, designated ME20-S, defined by monoclonal antibody ME20. Here we report the isolation and characterization of a cDNA clone that when transfected into COS cells directs the expression of ME20-M and ME20-S. This cDNA contains an open reading frame which encodes a 661-amino-acid-long precursor that contains a 23-amino-acid signal peptide and a 26-amino-acid transmembrane domain, separated by a hydrophilic region containing 5 potential Asn-linked and 14 predicted Pro-associated, Thr-linked glycosylation sites. The transmembrane domain is followed by a carboxy-terminal 45-amino-acid putative intracellular domain rich in Ser residues. Analysis of ME20-M by amino acid sequencing identified the proteolytic processing site. Signal peptide cleavage occurs at the Thr-24-Lys-25 peptide bond of the precursor and results in the 637-amino-acid ME20-M with a calculated molecular weight of 67,782. ME20-M is derived from a single 3.3- to 3.4-kb mRNA transcript that is expressed at varying levels in melanoma cell lines, correlating with immunofluorescence determination of protein expression. The amino acid sequence of the ME20 antigen deduced from the cDNA differs from the human neonatal melanocyte-specific Pmel 17 gene product by a single amino acid substitution and deletion of 7 amino acid residues, and it is 80% homologous with the bovine retinal pigment RPE1 cDNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cloning and expression of the gene for the melanoma-associated ME20 antigen. 817 25

A murine monoclonal antibody, ME20, with high selectivity for melanomas, has been utilized to isolate a unique membrane-bound (designated ME20-M) and secreted (designated ME20-S) antigen from H3606 human melanoma cells. ME20-M was purified from the cell lysate and ME20-S from the conditioned medium of H3606 cells by immunoaffinity chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The apparent molecular weights were 105,000 and 76,000, respectively. Analyses of ME20-M and ME20-S by amino acid sequencing identified the processing sites. Signal peptide cleavage occurs at Thr-24 of pro-ME20 antigen, yielding ME20-M (25 to 661). In addition, proteolytic processing of the precursor at Val-467 yields ME20-S (25 to 467). We report the characterization of Asn-linked glycosylation sites in ME20-M and ME20-S to determine the involvement of oligosaccharides in the proteolytic processing of pro-ME20 antigen. Tryptic peptide maps of ME20-M and ME20-S were prepared and the glycosylation sites identified by sequence analyses. Oligosaccharides were enzymatically released and characterized by high-performance anion-exchange chromatography. We found high-mannose-type structures at Asn-57, Asn-82, and Asn-87 of ME20-M, whereas ME20-S contained 73% complex-type and 27% high-mannose-type oligosaccharides at the same sites. To assess the role of oligosaccharides in the processing of the ME20 antigen, we tested the effect of the oligosaccharide processing modifier deoxymannojirimycin, a compound that inhibits synthesis of hybrid- and complex-type oligosaccharides. Deoxymannojirimycin had no effect on the synthesis and relative rate of synthesis of ME20-M, but markedly reduced the synthesis of ME20-S without affecting the rate of secretion. The reported results suggest that carbohydrate maturation of the ME20 antigen may be important for processing and secretion.
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PMID:Differential processing and secretion of the melanoma-associated ME20 antigen. 818 25

The human melanoma tumor Ags, MART1 and gp100, are specifically recognized by HLA-A2-restricted CD8+ CTLs derived from melanoma patients and appear to be involved in tumor regression. In order to develop immunizing vectors for the treatment of patients with metastatic melanoma, replication-defective recombinant adenoviruses, Ad2CMV-MART1 and Ad2CMV-gp100, which encode these tumor Ags, have been generated. Infection of non-Ag expressing HLA-A2+ cell lines A375 and MDA-231 with the vectors resulted in recognition by Ag-specific CTLs as demonstrated by specific target cell lysis and release of cytokines, including IFN-gamma, TNF-alpha, and granulocyte-macrophage-CSF. Sodium butyrate and TNF-alpha can further augment adenovirus-mediated transgene expression and increase recognition by specific CTLs. Although adenovirus-infected cells expressed the E3/19K protein at detectable levels, significant reduction of surface MHC class I expression was observed in only 3 of 10 tumor cell lines infected with either Ad2CMV-MART1 or Ad2CMV-gp100. Because of the suspected homology between the human MART1 and gp100 genes and their murine counterparts, we immunized C57BL/6 mice with these recombinant adenoviruses and demonstrated that immunization with Ad2CMV-gp100 could protect mice from murine melanoma B16 challenge administered intradermally. Depletion of CD8+ but not CD4+ T cells in vivo from Ad2CMV-gp100-vaccinated mice eliminated the protective effect. The anti-gp100 T cells induced by Ad2CMV-gp100 vaccinated appeared to be responsible for the protection. Thus, these recombinant adenoviruses encoding tumor Ags may be useful as vaccines to induce specific T cell immunity for cancer therapy.
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PMID:Antigen-specific tumor vaccines. Development and characterization of recombinant adenoviruses encoding MART1 or gp100 for cancer therapy. 854 23

Tumor rejection antigens, recognized by cytotoxic T lymphocytes (CTL), have been identified in several tumors. In malignant melanoma MAGE-1 and -3 antigen peptides, recognized by specific CTL, were defined. Tyrosinase, gp100 and Melan A/MART-1, normally expressed in the melanosome, were also shown to be recognized by specific CTL. In murine tumors, three antigenic peptides were identified. These are P1A in mastocytoma P815, MUT1 in murine lung carcinoma (3LL) derived from connexin 37, and pRL1 in murine leukemia RL male 1 derived from c-akt proto-oncogene. Analysis of the tumor rejection antigen peptides will elucidate the molecular nature of the tumor rejection antigen and facilitate their therapeutic use as tumor vaccine.
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PMID:[Analysis of tumor rejection antigen peptides recognized by specific CTL]. 858 97

We have determined the DNA sequence and genomic organization of D12S53E (Pmel 17), the human homologue of the mouse silver (si) locus. D12S53E encodes a melanosomal matrix protein whose expression is closely correlated with cellular melanin content and which is a frequent melanoma tumor antigen recognized by cytotoxic T lymphocytes. D12S53E is a likely candidate gene for some cases of human oculocutaneous albinism not associated with known albinism loci.
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PMID:Genomic organization and sequence of D12S53E (Pmel 17), the human homologue of the mouse silver (si) locus. 859 76

To determine whether HLA-A21 restricted melanoma Ags exist that are not expressed on normal melanocytes, a panel of 478 T cell clones from six HLA-A21+ patients was selected for HLA-A2 restricted lysis of autologous tumor and then tested for differential recognition of HLA-A2.1+ melanomas and normal melanocytes. Four subsets of clones were identified in the panel of 107 HLA-A2-restricted CTL clones. CTL clones from three of the four subsets did not lyse melanocytes, but recognized fresh HLA-A2.1+ melanomas and defined three classes of epitopes, including unique Ags, common melanoma Ags, and Ags shared with neoplastic cells of different histologic origin. These CTL clones did not recognize any of the 10 peptides selected for specific association to HLA-A2.1 and derived from Melan-A/Mart-1, tyrosinase, gp100, or MAGE-3 proteins. By contrast, the fourth subset of HLA-A2.1-restricted CTl clones recognized both melanoma and melanocytes. These CTL clones were directed to a peptide from either Melan-A/Mart-1, tyronise, or gp100. By a limiting dilution assay, designed to evaluate the frequency of HLA-A2-restricted CTL precursors (CTLp) directed to melanoma but not to melanocytes, such precursors were found in the peripheral blood or tumor site of five of six HLA-A2.1+ melanoma patients, and their frequency was much higher than the frequency of CTLp recognizing both tumor cells and the melanocytes. These results suggest that in melanoma patients most of the HLA-A2.1-restricted immune repertoire to melanoma is directly to epitopes expressed in the neoplastic but not in the normal cells of the melanocyte lineage.
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PMID:Cytotoxic T cells directed to tumor antigens not expressed on normal melanocytes dominate HLA-A2.1-restricted immune repertoire to melanoma. 859 64

Peptide epitopes derived from differentiation antigens of the melanocyte lineage have been identified in human melanomas and normal cultured melanocytes as targets for MHC-restricted cytotoxic T lymphocytes (CTL). Characterization of multiple CTL-defined antigenic determinants and the presence of corresponding precursor CTL open perspectives for the development of antigen-based vaccines. In the present study, we determined the CTL reactivity against melanoma-associated peptides derived from Melan A/MART-1, tyrosinase and gp100/Pmel17 in 10 HLA-A2+ melanoma patients and 10 healthy individuals. Then, we examined the immunological effects and toxicity of intradermal inoculation of synthetic melanoma-associated peptides. Six patients with advanced melanoma received weekly intradermal injections of 6 melanoma-associated peptides and the influenza matrix peptide as a control for 4 consecutive weeks. DTH reactions were observed in 5/6 patients at the injections sites of the tyrosinase signal peptide and of the influenza matrix peptide. No toxic side effects were observed. Changes in CTL reactivity after peptide vaccination were assessed by an MLPC assay for each peptide. Generation of peptide-specific CTL was documented against Melan A/MART-1-derived peptide epitopes, the tyrosinase signal peptide and the influenza matrix peptide after vaccination. A decreasing CTL response against the internal tyrosinase peptide was documented in 1 patient through the course of vaccination and a decrease in DTH reactions. No major tumor regressions were observed. Two patients with rapidly progressive disease before vaccination have shown disease stabilization since vaccinations started. In conclusion, our results demonstrate that peptide alone injected intradermally may generate antigen-specific DTH reactions and an increase of antigen-specific CTL reactivity.
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PMID:Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo: implications for tumor vaccines with melanoma-associated antigens. 860 5


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