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)

Glycosylation inhibitors, glucosamine or tunicamycin, have been found to be specific inhibitory modulators for melanogenesis, which is accentuated generally in malignant melanoma cells. Exposure to glucosamine (1 mg/ml) or tunicamycin (0.2 to 0.4 micrograms/ml) induces a marked pigment loss within melanoma cells in vitro with a decrease in their grown curves. This melanogenic inhibition occurs without a substantial decrease in the synthesis of DNA, RNA, and protein in comparison with a specific, marked suppression of carbohydrate synthesis as revealed by suppressed mannose incorporation into these cells. Assay of tyrosinase of glucosamine- or tunicamycin-induced unpigmented melanoma cells has revealed a selective and marked decrease in the melanosome-rich large-granule fraction, but no substantial decrease in the total activity of remaining subcellular fractions. Electrophoresis of tyrosinase in the 30,000 X g supernatant fraction demonstrates an increase in the T1 form of soluble tyrosinase, while a disappearance of or marked decrease in membrane-bound tyrosinase, T3, is seen in the small- and large-granule fractions. Glycoprotein synthesis in the melanogenic subcellular compartments of pigment cells seems to play an integral role in melanogenesis which is principally enhanced in their carcinogenic status.
Cancer Res 1982 May
PMID:Loss of melanogenic properties in tyrosinases induced by glucosylation inhibitors within malignant melanoma cells. 680 85

The effects of theophylline and melanocyte-stimulating hormone on B16 melanoma cells in culture cells were studied by electron microscopy and dopa cytochemistry. The data show that theophylline and melanocyte-stimulating hormone enhance melanogenesis by activating tyrosinase synthesis and its transfer but that neither affects the synthesis of the well-organized eumelanosome matrix. Their pigmenting effects appear to be limited to the melanogenic cells and result from a marked increase, particularly in theophylline-treated cells, in pheomelanosome formation.
Cancer Res 1982 Jul
PMID:Electron microscopic and cytochemical observations of theophylline and melanocyte-stimulating hormone effects on melanoma cells in culture. 680 46

Two melanoma cell lines, each derived from a different patient with metastatic disease, were very similar in their appearance, their growth characteristics, and their tendency to differentiate and to pigment in culture as they become confluent. These lines, UCT-Mel 1 and UCT-Mel 2, were used to study the effects of retinoic acid and other derivatives of vitamin A. When added to UCT-Mel 1 cells, retinoids had only a modest effect on plasminogen activator release and were without measurable effect on morphology, growth, or tyrosinase synthesis. In contrast, when added to UCT-Mel 2 cells, retinoids appeared to induce a more differentiated state evident as an inhibition of cell proliferation and the assumption of a dendritic morphology. Paradoxically, however, retinoids caused a striking inhibition of the density-dependent intracellular accumulation of tyrosinase and melanin that was taken to represent spontaneous in vitro differentiation. Culture of UCT-Mel 2 cells in the presence of retinoic acid resulted in initial inhibition followed by marked stimulation of cellular plasminogen activator release. The data suggest that the manner in which retinoids exert their effects on cells in vitro does not depend on the histological origin of the tumor cells being studied but on the innate responsiveness of that particular cell line to the retinoid or compound in question.
Cancer Res 1982 Dec
PMID:Variable effects of retinoids on two pigmenting human melanoma cell lines. 681 52

The incorporation of [2-14C]-2-thiouracil and a series of [125I]-5-iodo-2-thiouracils ([125I]ISUra(s)) into cultured Greene hamster melanoma cells was determined in order to establish their properties as false precursors in the melanin-biosynthetic pathway. The cold trichloroacetic acid-precipitable incorporation of [2-14C]-2-thiouracil as well as [125I]ISUra into melanoma cells after a 24- to 48-hr labeling period proved to be completely tyrosinase dependent (more than 99.5% inhibition could be achieved by 0.5 mM phenylthiourea). [125I]ISUra incorporation was 3-fold higher than was [2-14C]-2-thiouracil incorporation and was enhanced by 1 mM theophylline treatment. [125I]ISUra incorporation into hamster, rabbit, and human melanoma cells showed a linear relationship with cell melanin content. Methylation of the sulfur completely prevented the incorporation, while propylation but not methylation at position 6 resulted in lower incorporation. [125I]ISUra proved to be a marker for melanogenesis and may be useful in studies on the differentiation of cultured melanoma cells.
Cancer Res 1983 Mar
PMID:Incorporation of [125I]-5-iodo-2-thiouracil in cultured hamster, rabbit, and human melanoma cells. 682 1

Human malignant melanoma cell lines have been divided into three broad groups on the basis of morphology, pigmentation, tyrosinase levels, the 2-dimensional electrophoretic patterns of their [3H]glucosamine-labeled glycoproteins and the presence or absence of an extracellular matrix of fibronectin. The most pigmented cell lines were characterized by the synthesis of a novel glycoprotein with a molecular weight of 75,000 and the absence of a fibronectin matrix. As cultured skin melanocytes also had these characteristics, this group of melanomas appears to be the most differentiated. Melanoma cell lines in the amelanotic group were characterized by the synthesis of high levels of HLA-DR antigen and by the production of an extracellular fibronectin matrix.
Cancer Res 1983 Jun
PMID:Glycoproteins as differentiation markers in human malignant melanoma and melanocytes. 685 May 92

Cutaneous melanomas of Tyr-SV40E transgenic mice (mice whose transgene consists of the tyrosinase promoter fused to the coding regions of simian virus 40 early genes) strikingly resemble human melanomas in their development and progression. Unlike human melanomas, the mouse tumors all arise in genetically identical individuals, thereby better enabling expression of specific genes to be characterized in relation to advancing malignancy. The products of pigment genes are of particular interest because peptides derived from these proteins have been reported to function as autoantigens with immunotherapeutic potential in some melanoma patients. However, the diminished pigmentation characteristic of many advanced melanomas raises the possibility that some of the relevant products may no longer be expressed in the most malignant cells. We have therefore investigated the contributions of several pigment genes in melanotic vs. relatively amelanotic components of primary and metastatic mouse melanomas. The analyses reveal marked differences within and among tumors in levels of mRNAs and proteins encoded by the wild-type alleles at the albino, brown, slaty, and silver loci. Tyrosinase (the protein encoded by the albino locus) was most often either absent or undetectable as melanization declined. The protein encoded by the slaty locus (tyrosinase-related protein 2) was the only one of those tested that was clearly present in all the tumor samples. These results suggest that sole reliance on targeting tyrosinase-based antigens might selectively favor survival of more malignant cells, whereas targeting the ensemble of the antigens tested might contribute toward a more inclusive and effective antimelanoma strategy.
 ...
PMID:Changes in expression of putative antigens encoded by pigment genes in mouse melanomas at different stages of malignant progression. 747 44

Peptides of melanosomal proteins have recently been shown to be recognized in an HLA-restricted mode by specific cytolytic T lymphocytes in melanoma patients. Dendritic antigen-presenting cells (DC) are considered to be the most effective stimulators of T cell responses, and the use of these cells has therefore been proposed to generate therapeutic responses to tumor antigens in cancer patients. We, therefore, generated DC from peripheral blood of normal donors in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. Flow cytometric analysis of the cells during a 2-week culture revealed a loss of CD14 and CD34 expression, a concomittent increase of CD1a, CD11a,b and c, CD44, CD45, CD54, HLA-class I and II, and intermediate levels of CD26, CD80 and CD86. Cultured DC stimulated proliferation of allogeneic T cells and induced a marked, up to 20-fold, stimulation of T cell proliferation after pulsing with tetanus toxoid. To achieve independence of already-identified antigenic peptides presented in HLA class I-restricted fashion, which limits the general applicability of such peptides for vaccination of melanoma patients, we tested whether DC are transfectable with eukaryotic expression plasmids. DC transfected with two reporter genes (CAT, beta-galactosidase) using a liposome-based transfection technique, exhibited only low levels of enzymatically active proteins, but were able to degrade rapidly intracellular proteins and to process peptides efficiently. Chloramphenicol acetyltransferase as well as tyrosinase mRNA were detectable after transfection by reverse-transcriptase-polymerase chain reaction, and enzyme activities became measurable. Furthermore, DC transfected with the tyrosinase gene were able to induce specific T cell activation in vitro, indicating appropriate peptide processing and presentation in DC after transfection. These data suggest new approaches to future tumor vaccination strategies.
 ...
PMID:Dendritic cells generated from peripheral blood transfected with human tyrosinase induce specific T cell activation. 748 49

MHC class I-restricted CTLs specific for antigens expressed by malignant cells are an important component of immune responses against human cancer. Recently, in melanoma a number of melanocyte differentiation antigens have been identified as potential tumor rejection antigens. In the present study, we show that by applying peptide-loaded dendritic cells, induced by granulocyte-macrophage colony-stimulating factor and interleukin 4 from peripheral blood monocytes of healthy donors, we were able to elicit melanoma-associated antigen-specific CTL in vitro. We demonstrate the induction of CTLs directed against HLA-A2.1 presented epitopes derived from tyrosinase, gp100, and Melan A/MART-1. Apart from lysis of peptide-loaded target cells, these CTLs displayed reactivity with HLA-A2.1+ melanoma tumor cell lines and cultured normal melanocytes endogenously expressing the target antigen. These data indicate that these CTLs recognize naturally processed and presented epitopes and that precursor CTLs against melanocyte differentiation antigens are present in healthy individuals. The ability to generate tumor-specific CTLs in vitro, using granulocyte-macrophage colony-stimulating factor/interleukin 4-induced dendritic cells, illustrates the potential use of this type of antigen-presenting cells for vaccination protocols in human cancer.
Cancer Res 1995 Nov 15
PMID:Generation of antimelanoma cytotoxic T lymphocytes from healthy donors after presentation of melanoma-associated antigen-derived epitopes by dendritic cells in vitro. 758 96

Since response rates in human melanoma are low with currently available therapeutic modalities, we have reevaluated the potential usefulness of retinoids as new alternatives for therapy of metastatic melanoma. Nine synthetic retinoids with high affinity and/or selectivity for the retinoic acid receptors (RAR) alpha, beta, and gamma were studied in comparison to all-trans retinoic acid (RA) for their in vitro effects on melanoma cell proliferation and for their immunomodulating capacities using four human melanoma cell lines. Eight out of ten retinoids tested had no effect on melanoma cell growth, whereas the remaining two compounds with high RAR-gamma selectivity (CD437 and CD2325) showed a dose-dependent antiproliferative effect on all melanoma cell lines with IC50 (concentration inhibiting response by 50%) values between 10(-6) and 10(-7)M. Further analyses showed that paracrine-mediated tumor cell growth inhibition such as induction of transforming growth factor (TGF)-beta described as one mechanism of retinoid action and enzyme systems such as tyrosinase and monoamine oxidase were not involved in mediating the antiproliferative effects exerted by the two retinoids. Four of nine retinoids modulated HLA-DR expression on human melanoma cells, and expression levels of intercellular adhesion molecule 1 (ICAM-1) was increased by another subset of compounds. These effects were, however, not correlated to the receptor selectivity of the retinoids. The potent growth inhibitory effect of the RAR-gamma-selective retinoids and the immunomodulating capacities of the retinoids open an interesting alternative for new antiproliferative and immunomodulatory strategies in the treatment of metastatic melanoma.
Recent Results Cancer Res 1995
PMID:Effects of various synthetic retinoids on proliferation and immunophenotype of human melanoma cells in vitro. 759 89

We used a gene transfer-based system to generate highly toxic purine bases in tumor cells transfected with the Escherichia coli purine nucleoside phosphorylase (PNP) gene. Because these toxic purines are membrane permeant, they mediate effective killing of neighboring cells that do not express E. coli PNP ("bystander" toxicity). In mixed cultures containing increasing percentages of cells with gene expression, 100% cancer cell growth arrest and total population killing was demonstrated when as few as 1-2% of cells expressed E. coli PNP. We used E. coli PNP to test bystander killing of human melanoma cells. A 529-bp region upstream of the human tyrosinase gene start site was shown to direct melanoma-specific expression in human cell lines. When this human tyrosinase regulatory region was used to control E. coli PNP expression, profound toxicity was observed in melanoma cells after treatment with the relatively nontoxic substrate 6-methylpurine-deoxyriboside, which is converted by E. coli PNP into the highly toxic purine base 6-methylpurine. Bystander toxicity was estimated as at least 100 cells killed for each cell expressing E. coli PNP, a level substantially higher than that of other tumor sensitization genes currently being used in clinical trails. These results suggest that the high bystander activity of the system could lead to significant antimelanoma responses in vivo.
Cancer Res 1995 Aug 01
PMID:Bystander killing of melanoma cells using the human tyrosinase promoter to express the Escherichia coli purine nucleoside phosphorylase gene. 761 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>