Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0268596 (EMA)
 2,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During a systematic, immunocytochemical screening of 40 human cutaneous melanomas (30 primary and 10 metastatic) for immunophenotype (IP) heterogeneity, we employed a library of 20 well characterized, commercially available mono- and polyclonal antibodies. The use of the sensitive, indirect, four to six step immunoperoxidase or alkaline phosphatase conjugated streptavidin-biotin antigen detection technique provided excellent results. The immunocytochemically most characteristic IP for primary cutaneous melanoma, as detected by us was: HMB45+, S-100+, CEA+, vimentin+, cytokeratin 19+, p53+, Rbgene+, nm23+, HLA-DR+, HL.A-DP+, c-erbB3/HER-3+/-, cytokeratin 10/13+/-, HLA-DQ-, cytokeratin 5/8-, EMA-, c-myc-, and actin-. During melanoma progression, a tendency toward poor differentiation (dedifferentiation) and an increase in c-myc expression have both been observed, the latter downregulating HLA-A,B,C expression and consequently diminishing the possibility of melanoma cell Iysis by powerful CD8+, cytotoxic T lymphocytes (CTL) or other cytotoxic cells which requires HLA class I antigens. The development of the metastatic potential in melanomas caused an increase in CEA expression, eliminated the presence of nm23, and prompted the appearance of actin among the intermediate filaments, composing the cytoskeleton of these malignant tumor cells. The most characteristic IP for MMs, identified by this study was HMB45+, S-100+, CEA+, EMA+, vimentin+, HLA-DR+, HLA-DP+, cytokeratin 19+, actin-, c-erbB3/HER-3+, p53+, cytokeratin 10/13+/-, c-myc+/-, c-erbB2/HER-2+/-, HLA-DQ-, cytokeratin 5/8-, Rb gene-, nm23-. It has been observed that adhesion molecules and integrins play a significant role in the complex process of melanoma metastasis and thus we propose a blocking of these de novo expressed molecules with the appropriate antibodies as a form of immunotherapy of PMs and early stages of MMs.
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PMID:Immunophenotypically varied cell subpopulations in primary and metastatic human melanomas. Monoclonal antibodies for diagnosis, detection of neoplastic progression and receptor directed immunotherapy. 861 65

Therapeutic approaches for cutaneous melanoma are flourishing, but despite promising results, there is an increasing number of reported primary or secondary resistance to the growing sets of drugs approved for therapy in the clinics. Combinatorial approaches may overcome resistance, as they may tackle specific weaknesses of melanoma cells, not sufficient on their own, but effective in combination with other therapies. The transgenic zebrafish line kita:ras develops melanoma with high frequency. At 3 dpf, transgenic kita:ras larvae show a hyperpigmentation phenotype as earliest evidence of abnormal melanocyte growth. Using this model, we performed a chemical screen based on automated detection of a reduction of melanocyte number caused by any of 1280 FDA or EMA approved drugs of the library. The analysis showed that 55 molecules were able to reduce by 60% or more the number of melanocytes per embryo. We further tested two compounds for each of the 5 classes, and a farnesyltransferase inhibitor (Lonafarnib), that inhibits an essential post-translational modification of HRAS and suppresses the hyperpigmentation phenotype. Combinations of Clotrimazole and Lonafarnib showed the most promising results in zebrafish embryos, allowing a dose reduction of both drugs. We performed validation of these observations in the metastatic human melanoma cell line A375M, and in normal human epithelial melanocytes (NHEM) in order to investigate the mechanism of action of Clotrimazole in blocking the proliferation of transformed melanocytes. Viability assay and analysis of energy metabolism in Clotrimazole treated cells show that this drug specifically affects melanoma cells in vitro and transformed melanocytes in vivo, having no effects on NHEM or wild type larvae. Similar effects were observed with another hit of the same class, Miconazole. Furthermore, we show that the effects of Clotrimazole are mediated by the inhibition of hexokinase activity, which is lethal to the abnormal metabolic profile of melanoma cells in vitro and in vivo. Thus, our study shows that the zebrafish can provide a phenotype-rich assay for fully automated screening approaches to identify drugs for synthetic lethal treatment in melanoma and suggest further testing of Clotrimazole in combinatorial treatments.
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PMID:Automated in vivo screen in zebrafish identifies Clotrimazole as targeting a metabolic vulnerability in a melanoma model. 3099 7