Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of apoptosis has been demonstrated previously by overexpression of CD95 ligand (CD95L) in cultured human melanoma cells. For in vivo approaches based on CD95L, however, targeted expression is a prerequisite and tyrosinase promoters have been considered for selection. Luciferase reporter gene assays performed for a representative panel of melanoma cell lines characterized by strong (SK-Mel-19), moderate (SK-Mel-13, MeWo), weak (A-375), and missing expression (M-5) of endogenous tyrosinase revealed high tyrosinase promoter activities in SK-Mel-19, SK-Mel-13, and MeWo, but only weak activities in A-375 and M-5 as well as in non-melanoma cell lines. After transfection of a CMV promoter CD95L expression construct, melanoma cells were found highly sensitive, as compared with non-melanoma cells. By applying a tyrosinase promoter CD95L construct, apoptosis was selectively induced in SK-Mel-19, SK-Mel-13, MeWo as well as in A-375, which was characterized by high CD95 surface expression and high sensitivity to agonistic CD95 activation. M5 and non-melanoma cell lines remained uninfluenced. Also, resistance to agonistic CD95 activation seen in MeWo characterized by weak CD95 surface expression was overcome by overexpression of CD95L. Our investigations provide evidence that tyrosinase promoter CD95L constructs may be of value for selective induction of apoptosis in therapeutic strategies for melanoma.
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PMID:Selective induction of apoptosis in melanoma cells by tyrosinase promoter-controlled CD95 ligand overexpression. 1565 77

The high mortality of melanoma demands the development of new strategies, and gene therapy may be considered provided improvements in efficacy and selectivity. Overexpression of the death ligand CD95L/FasL has been shown in previous studies as highly effective for apoptosis induction in melanoma cells. For efficient and selective targeting of melanoma, a conditional replication-competent adenoviral vector was constructed (Ad5-FFE-02), which drives CD95L expression by a tetracycline-inducible promoter. For restricting its replication to melanoma cells, the adenoviral E1A gene is controlled by a tyrosinase-derived promoter. Furthermore, adenoviral E1B was deleted and a mutated E1A was used to preferentially support replication in tumor cells. Proving its high selectivity and efficiency, strong expression of E1A and doxycycline-dependent induction of CD95L were characteristic for tyrosinase-positive melanoma cells after Ad5-FFE-02 transduction, whereas absent in non-melanoma cell lines. Importantly, Ad5-FFE-02-mediated cell lysis was restricted to melanoma cells, and induction of apoptosis was found only in tyrosinase and CD95 expressing cells. Finally, the combination of adenoviral replication and CD95L-mediated apoptosis resulted in an enhanced repression of melanoma cell growth. This new adenoviral vector may provide a basis for an efficient targeting of melanoma.
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PMID:Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication-competent CD95L adenovirus. 1972 69

High mortality and therapy resistance of melanoma demand the development of new strategies, and overcoming apoptosis deficiency appears as particularly promising. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown high potential for apoptosis induction in melanoma cells and may be applicable for gene therapy because of its selective impact on tumor cells. We have constructed a conditional replication-competent adenoviral vector with TRAIL controlled by a tetracycline-inducible promoter (AdV-TRAIL). A variant E1A protein and the lack of E1B aimed at the restriction of viral replication to tumor cells. In particular, the replication gene E1A is controlled by a tyrosinase promoter with high selectivity for melanoma cells. AdV-TRAIL mediated strong expression of E1A and doxycycline-dependent induction of TRAIL selectively in melanoma cells, which resulted in tumor cell lysis and induction of apoptosis. In contrast, non-melanoma cells and normal human melanocytes appeared to be protected. Comparison of the AdV-TRAIL approach with a comparable CD95L vector revealed similar efficacy in vitro. In mouse xenotransplantation models, AdV-TRAIL demonstrated its activity by significant melanoma growth reduction. Melanoma cell killing by AdV-TRAIL was further improved in vitro by combinations with chemotherapeutics. We demonstrate that melanoma cells may be efficiently targeted by TRAIL-based gene therapy, and resistance may be overcome by combined chemotherapy.
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PMID:Efficient melanoma cell killing and reduced melanoma growth in mice by a selective replicating adenovirus armed with tumor necrosis factor-related apoptosis-inducing ligand. 2097 3